Imidazopyridine derivatives as modulators of TNF activity

ABSTRACT

A series of substituted 3H imidazo[4,5-b]pyridine derivatives of formula (I), being potent modulators of human TNFa activity, are accordingly of benefit in the treatment and/or prevention of various human ailments, including autoimmune and inflammatory disorders; neurological and neurodegenerative disorders; pain and nociceptive disorders; cardiovascular disorders; metabolic disorders; ocular disorders; and oncological disorders.

This application is the U.S. national phase under 35 U.S.C. § 371 ofinternational application PCT/EP2014/076848, filed Dec. 8, 2014, whichclaims priority to GB application 1321741.9, filed Dec. 9, 2013.

The present invention relates to a class of fused imidazole derivatives,and to their use in therapy. More particularly, this invention isconcerned with pharmacologically active substituted3H-imidazo[4,5-b]pyridine derivatives. These compounds are modulators ofthe signalling of TNFα, and are accordingly of benefit as pharmaceuticalagents, especially in the treatment of adverse inflammatory andautoimmune disorders, neurological and neurodegenerative disorders, painand nociceptive disorders, cardiovascular disorders, metabolicdisorders, ocular disorders, and oncological disorders.

TNFα is the prototypical member of the Tumour Necrosis Factor (TNF)superfamily of proteins that share a primary function of regulating cellsurvival and cell death. One structural feature common to all knownmembers of the TNF superfamily is the formation of trimeric complexesthat bind to, and activate, specific TNF superfamily receptors. By wayof example, TNFα exists in soluble and transmembrane forms and signalsthrough two receptors, known as TNFR1 and TNFR2, with distinctfunctional endpoints.

Various products capable of modulating TNFα activity are alreadycommercially available. All are approved for the treatment ofinflammatory and autoimmune disorders such as rheumatoid arthritis andCrohn's disease. All currently approved products are macromolecular andact by inhibiting the binding of human TNFα to its receptor. Typicalmacromolecular TNFα inhibitors include anti-TNFα antibodies; and solubleTNFα receptor fusion proteins. Examples of commercially availableanti-TNFα antibodies include fully human antibodies such as adalimumab(Humira®) and golimumab (Simponi®), chimeric antibodies such asinfliximab (Remicade®), and pegylated Fab′ fragments such ascertolizumab pegol (Cimzia®). An example of a commercially availablesoluble TNFα receptor fusion protein is etanercept (Enbrel®).

TNF superfamily members, including TNFα itself, are implicated in avariety of physiological and pathological functions that are believed toplay a part in a range of conditions of significant medical importance(see, for example, M. G. Tansey & D. E. Szymkowski, Drug DiscoveryToday, 2009, 14, 1082-1088; and F. S. Carneiro et al., J. SexualMedicine, 2010, 7, 3823-3834).

The compounds in accordance with the present invention, being potentmodulators of human TNFα activity, are therefore beneficial in thetreatment and/or prevention of various human ailments. These includeautoimmune and inflammatory disorders; neurological andneurodegenerative disorders; pain and nociceptive disorders;cardiovascular disorders; metabolic disorders; ocular disorders; andoncological disorders.

In addition, the compounds in accordance with the present invention maybe beneficial as pharmacological standards for use in the development ofnew biological tests and in the search for new pharmacological agents.Thus, in one embodiment, the compounds of this invention may be usefulas radioligands in assays for detecting pharmacologically activecompounds. In an alternative embodiment, certain compounds of thisinvention may be useful for coupling to a fluorophore to providefluorescent conjugates that can be utilised in assays (e.g. afluorescence polarisation assay) for detecting pharmacologically activecompounds.

Co-pending international patent applications WO 2013/186229 (published19 Dec. 2013), WO 2014/009295 (published 16 Jan. 2014) and WO2014/009296 (also published 16 Jan. 2014) describe fused imidazolederivatives which are modulators of human TNFα activity.

None of the prior art available to date, however, discloses or suggeststhe precise structural class of 3H-imidazo[4,5-b]pyridine derivatives asprovided by the present invention.

The compounds in accordance with the present invention potently inhibitthe binding of a fluorescence conjugate to TNFα when tested in thefluorescence polarisation assay described herein. Indeed, when tested inthat assay, the compounds of the present invention exhibit an IC₅₀ valueof 50 μM or less, generally of 20 μM or less, usually of 5 μM or less,typically of 1 μM or less, suitably of 500 nM or less, ideally of 100 nMor less, and preferably of 20 nM or less (the skilled person willappreciate that a lower IC₅₀ figure denotes a more active compound).

Certain compounds in accordance with the present invention potentlyneutralise the activity of TNFα in a commercially available HEK-293derived reporter cell line known as HEK-Blue™ CD40L. This is a stableHEK-293 transfected cell line expressing SEAP (secreted embryonicalkaline phosphatase) under the control of the IFNβ minimal promoterfused to five NF-κB binding sites. Secretion of SEAP by these cells isstimulated in a concentration-dependent manner by TNFα. When tested inthe HEK-293 bioassay, also referred to herein as the reporter geneassay, certain compounds of the present invention exhibit an IC₅₀ valueof 50 μM or less, generally of 20 μM or less, usually of 5 μM or less,typically of 1 μM or less, suitably of 500 nM or less, ideally of 100 nMor less, and preferably of 20 nM or less (as before, the skilled personwill appreciate that a lower IC₅₀ figure denotes a more activecompound).

The present invention provides a compound of formula (I) or an N-oxidethereof, or a pharmaceutically acceptable salt or solvate thereof, or aglucuronide derivative thereof, or a co-crystal thereof:

wherein

E represents a covalent bond; or E represents —S(O)₂— or —N(R⁴)—; or Erepresents an optionally substituted straight or branched C₁₋₄ alkylenechain;

Q represents a covalent bond; or Q represents —O—, —S—, —S(O)—, —S(O)₂—,—S(O)(NR⁵)—, —N(R⁵)—, —C(O)N(R⁵)—, —N(R⁵)C(O)—, —S(O)₂N(R⁵)— or—N(R⁵)S(O)₂—; or Q represents an optionally substituted straight orbranched C₁₋₆ alkylene chain optionally comprising one, two or threeheteroatom-containing linkages independently selected from —O—, —S—,—S(O)—, —S(O)₂—, —S(O)(NR⁵)—, —N(R⁵)—, —C(O)N(R⁵)—, —N(R⁵)C(O)—,—S(O)₂N(R⁵)— and —N(R⁵)S(O)₂—;

Y represents C₃₋₇ cycloalkyl, aryl, C₃₋₇ heterocycloalkyl or heteroaryl,any of which groups may be optionally substituted by one or moresubstituents;

Z represents hydrogen, halogen or trifluoromethyl; or Z represents C₁₋₆alkyl, C₃₋₇ cycloalkyl, aryl, C₃₋₇ heterocycloalkyl, C₃₋₇heterocycloalkenyl or heteroaryl, any of which groups may be optionallysubstituted by one or more substituents; or Z represents —Z¹—Z² or—Z¹—C(O)—Z², either of which moieties may be optionally substituted byone or more substituents;

Z¹ represents a divalent radical derived from an aryl, C₃₋₇heterocycloalkyl or heteroaryl group;

Z² represents aryl, C₃₋₇ heterocycloalkyl, C₃₋₇ heterocycloalkenyl orheteroaryl;

R¹, R² and R³ independently represent hydrogen, halogen, cyano, nitro,hydroxy, trifluoromethyl, trifluoromethoxy, —OR^(a), —SR^(a), —SOR^(a),—SO₂R^(a), —SF₅, —NR^(b)R^(c), —NR^(c)COR^(d), —NR^(c)CO₂R^(d),—NHCONR^(b)R^(c), —NR^(c)SO₂R^(e), —N(SO₂R^(e))₂, —NHSO₂NR^(b)R^(c),—COR^(d), —CO₂R^(d), —CONR^(b)R^(c), —CON(OR^(a))R^(b), —SO₂NR^(b)R^(c)or —SO(NR^(b))R^(d); or C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇cycloalkyl, C₄₋₇ cycloalkenyl, C₃₋₇ cycloalkyl(C₁₋₆)alkyl, aryl,aryl(C₁₋₆)-alkyl, C₃₋₇ heterocycloalkyl, C₃₋₇heterocycloalkyl(C₁₋₆)alkyl, C₃₋₇ heterocycloalkenyl, C₄₋₉heterobicycloalkyl, heteroaryl, heteroaryl(C₁₋₆)alkyl,(C₃₋₇)heterocycloalkyl(C₁₋₆)alkyl-aryl-,heteroaryl(C₃₋₇)heterocycloalkyl-, (C₃₋₇)cycloalkyl-heteroaryl-,(C₃₋₇)cycloalkyl-(C₁₋₆)alkyl-hetero aryl-, (C₄₋₇)cyclo alkenyl-heteroaryl-, (C₄₋₉)bicycloalkyl-heteroaryl-,(C₃₋₇)heterocycloalkyl-heteroaryl-, (C₃₋₇)hetero cycloalkyl(C₁₋₆)alkyl-hetero aryl-, (C₃₋₇)heterocycloalkenyl-heteroaryl-,(C₄₋₉)heterobicycloalkyl-heteroaryl- or(C₄₋₉)spiroheterocycloalkyl-heteroaryl-, any of which groups may beoptionally substituted by one or more substituents;

R⁴ and R⁵ independently represent hydrogen or C₁₋₆ alkyl;

R^(a) represents C₁₋₆ alkyl, aryl, aryl(C₁₋₆)alkyl, heteroaryl orheteroaryl(C₁₋₆)alkyl, any of which groups may be optionally substitutedby one or more substituents;

R^(b) and R^(c) independently represent hydrogen or trifluoromethyl; orC₁₋₆ alkyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkyl(C₁₋₆)alkyl, aryl,aryl(C₁₋₆)alkyl, C₃₋₇ heterocycloalkyl, C₃₋₇heterocycloalkyl(C₁₋₆)alkyl, heteroaryl or heteroaryl(C₁₋₆)alkyl, any ofwhich groups may be optionally substituted by one or more substituents;or

R^(b) and R^(c), when taken together with the nitrogen atom to whichthey are both attached, represent azetidin-1-yl, pyrrolidin-1-yl,oxazolidin-3-yl, isoxazolidin-2-yl, thiazolidin-3-yl,isothiazolidin-2-yl, piperidin-1-yl, morpholin-4-yl, thiomorpholin-4-yl,piperazin-1-yl, homopiperidin-1-yl, homomorpholin-4-yl orhomopiperazin-1-yl, any of which groups may be optionally substituted byone or more substituents;

R^(d) represents hydrogen; or C₁₋₆ alkyl, C₃₋₇ cycloalkyl, aryl, C₃₋₇heterocycloalkyl or heteroaryl, any of which groups may be optionallysubstituted by one or more substituents; and

R^(e) represents C₁₋₆ alkyl, aryl or heteroaryl, any of which groups maybe optionally substituted by one or more substituents.

The present invention also provides a compound of formula (I) as definedabove or an N-oxide thereof, or a pharmaceutically acceptable salt orsolvate thereof, or a glucuronide derivative thereof, or a co-crystalthereof, for use in therapy.

The present invention also provides a compound of formula (I) as definedabove or an N-oxide thereof, or a pharmaceutically acceptable salt orsolvate thereof, or a glucuronide derivative thereof, or a co-crystalthereof, for use in the treatment and/or prevention of disorders forwhich the administration of a modulator of TNF a function is indicated.

In another aspect, the present invention provides a compound of formula(I) as defined above or an N-oxide thereof, or a pharmaceuticallyacceptable salt or solvate thereof, or a glucuronide derivative thereof,or a co-crystal thereof, for use in the treatment and/or prevention ofan inflammatory or autoimmune disorder, a neurological orneurodegenerative disorder, pain or a nociceptive disorder, acardiovascular disorder, a metabolic disorder, an ocular disorder, or anoncological disorder.

The present invention also provides a method for the treatment and/orprevention of disorders for which the administration of a modulator ofTNFα function is indicated which comprises administering to a patient inneed of such treatment an effective amount of a compound of formula (I)as defined above or an N-oxide thereof, or a pharmaceutically acceptablesalt or solvate thereof, or a glucuronide derivative thereof, or aco-crystal thereof.

In another aspect, the present invention provides a method for thetreatment and/or prevention of an inflammatory or autoimmune disorder, aneurological or neurodegenerative disorder, pain or a nociceptivedisorder, a cardiovascular disorder, a metabolic disorder, an oculardisorder, or an oncological disorder, which comprises administering to apatient in need of such treatment an effective amount of a compound offormula (I) as defined above or an N-oxide thereof, or apharmaceutically acceptable salt or solvate thereof, or a glucuronidederivative thereof, or a co-crystal thereof.

Where any of the groups in the compounds of formula (I) above is statedto be optionally substituted, this group may be unsubstituted, orsubstituted by one or more substituents. Typically, such groups will beunsubstituted, or substituted by one or two substituents.

For use in medicine, the salts of the compounds of formula (I) will bepharmaceutically acceptable salts. Other salts may, however, be usefulin the preparation of the compounds of use in the invention or of theirpharmaceutically acceptable salts. Standard principles underlying theselection and preparation of pharmaceutically acceptable salts aredescribed, for example, in Handbook of Pharmaceutical Salts: Properties,Selection and Use, ed. P. H. Stahl & C. G. Wermuth, Wiley-VCH, 2002.Suitable pharmaceutically acceptable salts of the compounds of use inthis invention include acid addition salts which may, for example, beformed by mixing a solution of the compound of use in the invention witha solution of a pharmaceutically acceptable acid such as hydrochloricacid, sulphuric acid, methanesulphonic acid, fumaric acid, maleic acid,succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid orphosphoric acid. Furthermore, where the compounds of use in theinvention carry an acidic moiety, e.g. carboxy, suitablepharmaceutically acceptable salts thereof may include alkali metalsalts, e.g. sodium or potassium salts; alkaline earth metal salts, e.g.calcium or magnesium salts; ammonium salts; and salts formed withsuitable organic ligands, e.g. quaternary ammonium salts, and megluminesalts.

The present invention includes within its scope solvates of thecompounds of formula (I) above. Such solvates may be formed with commonorganic solvents, e.g. hydrocarbon solvents such as benzene or toluene;chlorinated solvents such as chloroform or dichloromethane; alcoholicsolvents such as methanol, ethanol or isopropanol; ethereal solventssuch as diethyl ether or tetrahydrofuran; or ester solvents such asethyl acetate. Alternatively, the solvates of the compounds of formula(I) may be formed with water, in which case they will be hydrates.

The present invention also includes co-crystals within its scope. Thetechnical term “co-crystal” is used to describe the situation whereneutral molecular components are present within a crystalline compoundin a definite stoichiometric ratio. The preparation of pharmaceuticalco-crystals enables modifications to be made to the crystalline form ofan active pharmaceutical ingredient, which in turn can alter itsphysicochemical properties without compromising its intended biologicalactivity (see Pharmaceutical Salts and Co-crystals, ed. J. Wouters & L.Quere, RSC Publishing, 2012). Typical examples of co-crystal formers,which may be present in the co-crystal alongside the activepharmaceutical ingredient, include L-ascorbic acid, citric acid,glutaric acid, urea and nicotinamide.

The present invention includes within its scope prodrugs of thecompounds of formula (I) above. In general, such prodrugs will befunctional derivatives of the compounds of formula (I) which are readilyconvertible in vivo into the required compound of formula (I).Conventional procedures for the selection and preparation of suitableprodrug derivatives are described, for example, in Design of Prodrugs,ed. H. Bundgaard, Elsevier, 1985.

Suitable alkyl groups which may be present on the compounds of use inthe invention include straight-chained and branched C₁₋₆ alkyl groups,for example C₁₋₄ alkyl groups. Typical examples include methyl and ethylgroups, and straight-chained or branched propyl, butyl and pentylgroups. Particular alkyl groups include methyl, ethyl, n-propyl,isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, 2,2-dimethylpropyland 3-methylbutyl. Derived expressions such as “C₁₋₆ alkoxy”, “C₁₋₆alkylthio”, “C₁₋₆ alkylsulphonyl” and “C₁₋₆ alkylamino” are to beconstrued accordingly.

The expression “C₁₋₄ alkylene chain” refers to a divalent straight orbranched alkylene chain containing 1 to 4 carbon atoms. Typical examplesinclude methylene, ethylene, methylmethylene, ethylmethylene anddimethylmethylene.

Suitable C₂₋₆ alkenyl groups include vinyl and allyl.

Suitable C₂₋₆ alkynyl groups include ethynyl, propargyl and butynyl.

The term “C₃₋₇ cycloalkyl” as used herein refers to monovalent groups of3 to 7 carbon atoms derived from a saturated monocyclic hydrocarbon, andmay comprise benzo-fused analogues thereof. Suitable C₃₋₇ cycloalkylgroups include cyclopropyl, cyclobutyl, benzocyclobutenyl, cyclopentyl,indanyl, cyclohexyl and cycloheptyl.

The term “C₄₋₇ cycloalkenyl” as used herein refers to monovalent groupsof 4 to 7 carbon atoms derived from a partially unsaturated monocyclichydrocarbon. Suitable C₄₋₇ cycloalkenyl groups include cyclobutenyl,cyclopentenyl, cyclohexenyl and cycloheptenyl.

The term “C₄₋₉ bicycloalkyl” as used herein refers to monovalent groupsof 4 to 9 carbon atoms derived from a saturated bicyclic hydrocarbon.Typical bicycloalkyl groups include bicyclo[3.1.0]hexanyl,bicyclo[4.1.0]heptanyl and bicyclo[2.2.2]octanyl.

The term “aryl” as used herein refers to monovalent carbocyclic aromaticgroups derived from a single aromatic ring or multiple condensedaromatic rings. Suitable aryl groups include phenyl and naphthyl,preferably phenyl.

Suitable aryl(C₁₋₆)alkyl groups include benzyl, phenylethyl,phenylpropyl and naphthylmethyl.

The term “C₃₋₇ heterocycloalkyl” as used herein refers to saturatedmonocyclic rings containing 3 to 7 carbon atoms and at least oneheteroatom selected from oxygen, sulphur and nitrogen, and may comprisebenzo-fused analogues thereof. Suitable heterocycloalkyl groups includeoxetanyl, azetidinyl, tetrahydrofuranyl, dihydrobenzo-furanyl,dihydrobenzothienyl, pyrrolidinyl, indolinyl, isoindolinyl,oxazolidinyl, thiazolidinyl, isothiazolidinyl, imidazolidinyl,tetrahydropyranyl, chromanyl, tetrahydro-thiopyranyl, piperidinyl,1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl,piperazinyl, 1,2,3,4-tetrahydroquinoxalinyl,hexahydro-[1,2,5]thiadiazolo[2,3-a]pyrazinyl, homopiperazinyl,morpholinyl, benzoxazinyl, thiomorpholinyl, azepanyl, oxazepanyl,diazepanyl, thiadiazepanyl and azocanyl.

The term “C₃₋₇ heterocycloalkenyl” as used herein refers tomonounsaturated or polyunsaturated monocyclic rings containing 3 to 7carbon atoms and at least one heteroatom selected from oxygen, sulphurand nitrogen, and may comprise benzo-fused analogues thereof. Suitableheterocycloalkenyl groups include thiazolinyl, isothiazolinyl,imidazolinyl, dihydropyranyl, dihydrothiopyranyl and1,2,3,6-tetrahydropyridinyl.

The term “C₄₋₉ heterobicycloalkyl” as used herein corresponds to C₄₋₉bicycloalkyl wherein one or more of the carbon atoms have been replacedby one or more heteroatoms selected from oxygen, sulphur and nitrogen.Typical heterobicycloalkyl groups include 3-azabicyclo[3.1.0]hexanyl,2-oxa-5-azabicyclo[2.2.1]heptanyl, 6-azabicyclo[3.2.0]heptanyl,3-azabicyclo[3.1.1]heptanyl, 3-azabicyclo[4.1.0]heptanyl,2-oxabicyclo[2.2.2]octanyl, quinuclidinyl,2-oxa-5-azabicyclo[2.2.2]octanyl, 3-azabicyclo[3.2.1]octanyl,8-azabicyclo-[3.2.1]octanyl, 3-oxa-8-azabicyclo[3.2.1]octanyl,3,8-diazabicyclo[3.2.1]octanyl, 3,6-diazabicyclo[3.2.2]nonanyl,3-oxa-7-azabicyclo[3.3.1]nonanyl and 3,9-diazabicyclo-[4.2.1]nonanyl.

The term “C₄₋₉ spiroheterocycloalkyl” as used herein refers to saturatedbicyclic ring systems containing 4 to 9 carbon atoms and at least oneheteroatom selected from oxygen, sulphur and nitrogen, in which the tworings are linked by a common atom. Suitable spiroheterocycloalkyl groupsinclude 5-azaspiro[2.3]hexanyl, 5-azaspiro[2.4]-heptanyl,2-azaspiro[3.3]heptanyl, 2-oxa-6-azaspiro[3.3]heptanyl,2-oxa-6-azaspiro[3.4]-octanyl, 2-oxa-6-azaspiro[3.5]nonanyl,7-oxa-2-azaspiro[3.5]nonanyl, 2-oxa-7-azaspiro-[3.5]nonanyl and2,4,8-triazaspiro[4.5]decanyl.

The term “heteroaryl” as used herein refers to monovalent aromaticgroups containing at least 5 atoms derived from a single ring ormultiple condensed rings, wherein one or more carbon atoms have beenreplaced by one or more heteroatoms selected from oxygen, sulphur andnitrogen. Suitable heteroaryl groups include furyl, benzofuryl,dibenzofuryl, thienyl, benzothienyl, thieno[2,3-c]pyrazolyl,thieno[3,4-b][1,4]dioxinyl, dibenzothienyl, pyrrolyl, indolyl,pyrrolo[2,3-b]pyridinyl, pyrrolo[3,2-c]pyridinyl,pyrrolo[3,4-b]pyridinyl, pyrazolyl, pyrazolo[1,5-a]pyridinyl,pyrazolo[3,4-c/]pyrimidinyl, indazolyl, 4,5,6,7-tetrahydroindazolyl,oxazolyl, benzoxazolyl, isoxazolyl, thiazolyl, benzothiazolyl,isothiazolyl, imidazolyl, benzimidazolyl, imidazo[2,1-b]thiazolyl,imidazo[1,2-c]pyridinyl, imidazo[4,5-b]pyridinyl, purinyl,imidazo[1,2-c]pyrimidinyl, imidazo[1,2-c]pyrazinyl, oxadiazolyl,thiadiazolyl, triazolyl, [1,2,4]triazolo[1,5-c]-pyrimidinyl,benzotriazolyl, tetrazolyl, pyridinyl, quinolinyl, isoquinolinyl,naphthyridinyl, pyridazinyl, cinnolinyl, phthalazinyl, pyrimidinyl,quinazolinyl, pyrazinyl, quinoxalinyl, pteridinyl, triazinyl andchromenyl groups.

The term “halogen” as used herein is intended to include fluorine,chlorine, bromine and iodine atoms, typically fluorine, chlorine orbromine.

Where the compounds of formula (I) have one or more asymmetric centres,they may accordingly exist as enantiomers. Where the compounds of use inthe invention possess two or more asymmetric centres, they mayadditionally exist as diastereomers. The invention is to be understoodto extend to the use of all such enantiomers and diastereomers, and tomixtures thereof in any proportion, including racemates. Formula (I) andthe formulae depicted hereinafter are intended to represent allindividual stereoisomers and all possible mixtures thereof, unlessstated or shown otherwise. In addition, compounds of formula (I) mayexist as tautomers, for example keto (CH₂C═O)⇄enol (CH═CHOH) tautomersor amide (NHC═O)⇄hydroxyimine (N═COH) tautomers. Formula (I) and theformulae depicted hereinafter are intended to represent all individualtautomers and all possible mixtures thereof, unless stated or shownotherwise.

It is to be understood that each individual atom present in formula (I),or in the formulae depicted hereinafter, may in fact be present in theform of any of its naturally occurring isotopes, with the most abundantisotope(s) being preferred. Thus, by way of example, each individualhydrogen atom present in formula (I), or in the formulae depictedhereinafter, may be present as a ¹H, ²H (deuterium) or ³H (tritium)atom, preferably ¹H. Similarly, by way of example, each individualcarbon atom present in formula (I), or in the formulae depictedhereinafter, may be present as a ¹²C, ¹³C or ¹⁴C atom, preferably ¹²C.

In one aspect, the present invention provides a compound of formula (I)as depicted above or an N-oxide thereof, or a pharmaceuticallyacceptable salt or solvate thereof, or a glucuronide derivative thereof,or a co-crystal thereof, wherein

Q represents —O—, —S—, —S(O)—, —S(O)₂—, —S(O)(NR⁵)—, —N(R⁵)—,—C(O)N(R⁵)—, —N(R⁵)C(O)—, —S(O)₂N(R⁵)— or —N(R⁵)S(O)₂—; or Q representsan optionally substituted straight or branched C₁₋₆ alkylene chainoptionally comprising one, two or three heteroatom-containing linkagesindependently selected from —O—, —S—, —S(O)—, —S(O)₂—, —S(O)(NR⁵)—,—N(R⁵)—, —C(O)N(R⁵)—, —N(R⁵)C(O)—, —S(O)₂N(R⁵)— and —N(R⁵)S(O)₂—;

Z represents C₃₋₇ cycloalkyl, aryl, C₃₋₇ heterocycloalkyl, C₃₋₇heterocycloalkenyl or heteroaryl, any of which groups may be optionallysubstituted by one or more substituents; or Z represents —Z¹—Z² or—Z¹—C(O)—Z², either of which moieties may be optionally substituted byone or more substituents; and

E, Y, R¹, R², R³, R⁵, Z¹ and Z² are as defined above.

In another aspect, the present invention provides a compound of formula(I) as depicted above or an N-oxide thereof, or a pharmaceuticallyacceptable salt or solvate thereof, or a glucuronide derivative thereof,or a co-crystal thereof, wherein

R¹ represents halogen or cyano; or C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₇ cycloalkyl, C₄₋₇ cycloalkenyl, C₃₋₇ cycloalkyl(C₁₋₆)alkyl,aryl, aryl(C₁₋₆)alkyl, C₃₋₇ heterocycloalkyl, C₃₋₇heterocycloalkyl(C₁₋₆)alkyl, C₃₋₇ heterocycloalkenyl, C₄₋₉heterobicycloalkyl, heteroaryl, heteroaryl(C₁₋₆)alkyl,(C₃₋₇)heterocycloalkyl(C₁₋₆)alkyl-aryl-,heteroaryl(C₃₋₇)heterocycloalkyl-, (C₃₋₇)cycloalkyl-heteroaryl-,(C₃₋₇)cycloalkyl-(C₁₋₆)alkyl-hetero aryl-, (C₄₋₇)cyclo alkenyl-heteroaryl-, (C₄₋₉)bicycloalkyl-heteroaryl-,(C₃₋₇)heterocycloalkyl-heteroaryl-, (C₃₋₇)hetero cycloalkyl(C₁₋₆)alkyl-hetero aryl-, (C₃₋₇)heterocycloalkenyl-heteroaryl-,(C₄₋₉)heterobicycloalkyl-heteroaryl- or(C₄₋₉)spiroheterocycloalkyl-heteroaryl-, any of which groups may beoptionally substituted by one or more substituents; and

E, Q, Y, Z, R² and R³ are as defined above.

Where the compounds in accordance with the invention comprise anoptionally substituted straight or branched alkylene chain, typicalvalues thereof include methylene (—CH₂—), (methyl)methylene, ethylene(—CH₂CH₂—), (ethyl)methylene, (dimethyl)-methylene, (methyl)ethylene,propylene (—CH₂CH₂CH₂—), (propyl)methylene and (dimethyl)ethylene, anyof which chains may be optionally substituted by one or moresubstituents. Suitably, such chains are unsubstituted, monosubstitutedor disubstituted. Typically, such chains are unsubstituted ormonosubstituted. In one embodiment, such chains are unsubstituted. Inanother embodiment, such chains are monosubstituted. In a furtherembodiment, such chains are disubstituted.

Examples of typical substituents on the alkylene chain which may bepresent in a compound in accordance with the invention include halogen,cyano, trifluoromethyl, oxo, hydroxy, C₁₋₆ alkoxy, carboxy(C₁₋₆)alkoxy,trifluoromethoxy, amino, C₁₋₆ alkylamino, di(C₁₋₆)alkylamino, C₂₋₆alkylcarbonylamino, carboxy, benzyloxycarbonyl, tetrazolyl,aminocarbonyl, C₁₋₆ alkylaminocarbonyl and di(C₁₋₆)alkylaminocarbonyl.

Specific examples of suitable substituents on the alkylene chain whichmay be present in a compound in accordance with the invention includefluoro, cyano, trifluoromethyl, hydroxy, methoxy, carboxymethoxy, amino,acetylamino, carboxy, benzyloxycarbonyl and tetrazolyl.

In a first embodiment, E represents a covalent bond, whereby the integerY is attached directly to the imidazole ring.

In a second embodiment, E represents —S(O)₂— or —N(R⁴)—. In a firstaspect of that embodiment, E represents —S(O)₂—. In a second aspect ofthat embodiment, E represents —N(R⁴)—.

In a third embodiment, E represents an optionally substituted straightor branched C₁₋₄ alkylene chain. In a first aspect of that embodiment, Erepresents an optionally substituted methylene (—CH₂—) linkage. In asecond aspect of that embodiment, E represents an optionally substituted(methyl)methylene linkage. In a third aspect of that embodiment, Erepresents an optionally substituted (ethyl)methylene linkage.

Generally, E represents a covalent bond; or E represents —N(R⁴)—; or Erepresents an optionally substituted straight or branched C₁₋₄ alkylenechain.

Typically, E represents —N(R⁴)—; or E represents an optionallysubstituted straight or branched C₁₋₄ alkylene chain.

Suitably, E represents a covalent bond; or E represents —N(R⁴)—; or Erepresents methylene (—CH₂—), (methyl)methylene or (ethyl)methylene, anyof which groups may be optionally substituted by one or moresubstituents.

Generally, E represents —N(R⁴)—; or E represents methylene (—CH₂—) or(ethyl)methylene, either of which groups may be optionally substitutedby one or more substituents.

Appositely, E represents —N(R⁴)—, or optionally substituted methylene.

Selected examples of typical substituents on the linkage represented byE include halogen, trifluoromethyl, oxo, hydroxy, C₁₋₆ alkoxy,carboxy(C₁₋₆)alkoxy, trifluoromethoxy, amino, C₁₋₆ alkylamino,di(C₁₋₆)alkylamino, C₂₋₆ alkylcarbonylamino, carboxy, benzyloxycarbonyland tetrazolyl.

Specific examples of typical substituents on the linkage represented byE include fluoro, trifluoromethyl, oxo, hydroxy, methoxy,carboxymethoxy, trifluoromethoxy, amino, methylamino, dimethylamino,acetylamino, carboxy, benzyloxycarbonyl and tetrazolyl.

Typical values of E include —N(R⁴)—, —CH₂—, —C(O)—, —CH(OCH₃)—,—CH(OCH₂CO₂H)—, —CH(NHCOCH₃)—, —CH(CO₂benzyl)-, —CH(CH₃)— and—CH(CH₂CH₃)—; or E may represent a covalent bond.

Illustrative values of E include —CH₂— and —CH(CH₃)—.

Suitable values of E include —N(R⁴)— and —CH₂—. In one embodiment, Erepresents —N(R⁴)—. In another embodiment, E represents —CH₂—.

In another embodiment, E represents —C(O)—.

In another embodiment, E represents —CH(OCH₃)—.

In an additional embodiment, E represents —CH(CH₃)—. In a particularaspect of that embodiment, the —CH(CH₃)— linkage represented by E is inthe (R) stereochemical configuration.

In a further embodiment, E represents —CH(CH₂CH₃)—.

In a first embodiment, Q represents a covalent bond, whereby the integerZ is attached directly to the imidazole ring.

In a second embodiment, Q represents —O—, —S—, —S(O)—, —S(O)₂—,—S(O)(NR⁵)—, —N(R⁵)—, —C(O)N(R⁵)—, —N(R⁵)C(O)—, —S(O)₂N(R⁵)— or—N(R⁵)S(O)₂—. In a first aspect of that embodiment, Q represents —O—. Ina second aspect of that embodiment, Q represents —S—. In a third aspectof that embodiment, Q represents —S(O)—. In a fourth aspect of thatembodiment, Q represents —S(O)₂—. In a fifth aspect of that embodiment,Q represents —S(O)(NR⁵)—. In a sixth aspect of that embodiment, Qrepresents —N(R⁵)—. In a seventh aspect of that embodiment, Q represents—C(O)N(R⁵)—. In an eighth aspect of that embodiment, Q represents—N(R⁵)C(O)—. In a ninth aspect of that embodiment, Q represents—S(O)₂N(R⁵)—. In a tenth aspect of that embodiment, Q represents—N(R⁵)S(O)₂—.

In a third embodiment, Q represents an optionally substituted straightor branched C₁₋₆ alkylene chain optionally comprising one, two or threeheteroatom-containing linkages independently selected from —O—, —S—,—S(O)—, —S(O)₂—, —S(O)(NR⁵)—, —N(R⁵)—, —C(O)N(R⁵)—, —N(R⁵)C(O)—,—S(O)₂N(R⁵)— and —N(R⁵)S(O)₂—. In a first aspect of that embodiment, Qrepresents an optionally substituted straight or branched C₁₋₆ alkylenechain. In a second aspect of that embodiment, Q represents an optionallysubstituted straight or branched C₁₋₆ alkylene chain comprising oneheteroatom-containing linkage independently selected from —O—, —S—,—S(O)—, —S(O)₂—, —S(O)(NR⁵)—, —N(R⁵)—, —C(O)N(R⁵)—, —N(R⁵)C(O)—,—S(O)₂N(R⁵)— and —N(R⁵)S(O)₂—. In a third aspect of that embodiment, Qrepresents an optionally substituted straight or branched C₁₋₆ alkylenechain comprising two heteroatom-containing linkages independentlyselected from —O—, —S—, —S(O)—, —S(O)₂—, —S(O)(NR⁵)—, —N(R⁵)—,—C(O)N(R⁵)—, —N(R⁵)C(O)—, —S(O)₂N(R⁵)— and —N(R⁵)S(O)₂—. In a fourthaspect of that embodiment, Q represents an optionally substitutedstraight or branched C₁₋₆ alkylene chain comprising threeheteroatom-containing linkages independently selected from —O—, —S—,—S(O)—, —S(O)₂—, —S(O)(NR⁵)—, —N(R⁵)—, —C(O)N(R⁵)—, —N(R⁵)C(O)—,—S(O)₂N(R⁵)— and —N(R⁵)S(O)₂—. In a fifth aspect of that embodiment, Qrepresents an optionally substituted straight or branched C₁₋₆ alkylenechain comprising one, two or three heteroatom-containing linkagesindependently selected from —O—, —S—, —N(R⁵)—, —C(O)N(R⁵)— and—N(R⁵)C(O)—.

Typically, Q represents a covalent bond; or Q represents —S(O)— or—S(O)₂—; or Q represents an optionally substituted straight or branchedC₁₋₆ alkylene chain optionally comprising one or twoheteroatom-containing linkages selected from —O—, —S—, —N(R⁵)—,—C(O)N(R⁵)—, and —N(R⁵)C(O)—.

Selected examples of typical substituents on the linkage represented byQ include halogen, cyano, trifluoromethyl, hydroxy, C₁₋₆ alkoxy andamino.

Selected examples of suitable substituents on the linkage represented byQ include hydroxy.

Specific examples of typical substituents on the linkage represented byQ include fluoro, cyano, trifluoromethyl, hydroxy, methoxy and amino.

Specific examples of suitable substituents on the linkage represented byQ include hydroxy.

Suitably, Q represents a covalent bond; or Q represents —S(O)—, —S(O)₂—or —N(R⁵)—; or Q represents —CH₂—, —CH(F)—, —CF₂—, —CH(CN)—, —CH(CH₃)—,—CH(OH)—, —CH(CH₂OH)—, —CH(OCH₃)—, —CH(NH₂)—, —CH₂CH₂—, —CH(OH)CH₂—,—CH(OH)CF₂—, —CH(OCH₃)CH₂—, —CH₂O—, —CH(CH₃)O—, —C(CH₃)₂O—,—CH(CH₂CH₃)O—, —CH(CF₃)O—, —CH₂S—, —CH₂S(O)—, —CH₂S(O)₂—, —CH₂N(R⁵)—,—CH₂CH₂CH₂—, —CH(OH)CH₂CH₂—, —CH(OCH₃)CH₂CH₂—, —CH₂CH₂O—, —CH₂OCH₂—,—CH₂OCH(F)—, —CH₂OCF₂—, —CH₂OCH(CH₃)—, —CH(CH₃)OCH₂—, —CH₂OC(CH₃)₂—,—C(CH₃)₂OCH₂—, —CH₂SCH₂—, —CH₂S(O)CH₂—, —CH₂S(O)₂CH₂—, —CH₂CH₂N(R⁵)—,—CH₂N(R⁵)CH₂—, —CH₂N(R⁵)C(O)—, —CH₂CH₂OCH₂—, —CH₂CH₂N(R⁵)C(O)—,—CH₂OCH₂CH₂—, —CH₂OCH₂CF₂—, —CH₂OCH₂CH(CH₃)—, —CH₂OCH(CH₃)CH₂—,—CH₂OC(CH₃)₂CH₂—, —CH₂OCH₂CH(CH₃)CH₂—, —CH₂OCH₂CH₂O—, —CH₂OCH₂C(O)N(R⁵)—or —CH₂OCH₂CH₂OCH₂—.

Appositely, Q represents a covalent bond; or Q represents —CH₂—,—CH(CN)—, —CH(OH)—, —CH(OCH₃)—, —CH₂O—, —CH₂N(R⁵)— or —CH₂OCH₂—.

Appropriately, Q represents a covalent bond; or Q represents —CH₂—,—CH(OH)— or —CH₂O—.

Particular values of Q include —CH₂—, —CH(OH)—, —CH₂O—, —CH₂S— and—CH₂OCH₂—. In a first embodiment, Q represents —CH₂—. In a secondembodiment, Q represents —CH(OH)—. In a third embodiment, Q represents—CH₂O—. In a fourth embodiment, Q represents —CH₂S—. In a fifthembodiment, Q represents —CH₂OCH₂—.

Generally, Y represents C₃₋₇ cycloalkyl, aryl or heteroaryl, any ofwhich groups may be optionally substituted by one or more substituents.

Typically, Y represents aryl or heteroaryl, either of which groups maybe optionally substituted by one or more substituents.

In a first embodiment, Y represents optionally substituted C₃₋₇cycloalkyl. In one aspect of that embodiment, Y represents unsubstitutedC₃₋₇ cycloalkyl. In another aspect of that embodiment, Y representsmonosubstituted C₃₋₇ cycloalkyl. In a further aspect of that embodiment,Y represents disubstituted C₃₋₇ cycloalkyl.

In a second embodiment, Y represents optionally substituted aryl. In oneaspect of that embodiment, Y represents unsubstituted aryl. In anotheraspect of that embodiment, Y represents monosubstituted aryl. In afurther aspect of that embodiment, Y represents disubstituted aryl.

In a third embodiment, Y represents optionally substituted C₃₋₇heterocycloalkyl. In one aspect of that embodiment, Y representsunsubstituted C₃₋₇ heterocycloalkyl. In another aspect of thatembodiment, Y represents monosubstituted C₃₋₇ heterocycloalkyl. In afurther aspect of that embodiment, Y represents disubstituted C₃₋₇heterocycloalkyl.

In a fourth embodiment, Y represents optionally substituted heteroaryl.In one aspect of that embodiment, Y represents unsubstituted heteroaryl.In another aspect of that embodiment, Y represents monosubstitutedheteroaryl. In a further aspect of that embodiment, Y representsdisubstituted heteroaryl.

Suitably, Y represents benzocyclobutenyl, phenyl, thienyl, thiazolyl orpyridinyl, any of which groups may be optionally substituted by one ormore substituents.

Appropriately, Y represents phenyl, thienyl or thiazolyl, any of whichgroups may be optionally substituted by one or more substituents.

Appositely, Y represents phenyl, which may be optionally substituted byone or more substituents.

Examples of optional substituents which may be present on the moiety Yinclude one, two or three substituents independently selected fromhalogen, cyano, nitro, C₁₋₆ alkyl, trifluoromethyl, hydroxy, C₁₋₆alkoxy, difluoromethoxy, trifluoromethoxy, C₁₋₆ alkylthio, C₁₋₆alkylsulfinyl, C₁₋₆ alkylsulfonyl, (C₁₋₆)alkylsulfonyloxy, amino, C₁₋₆alkylamino, di(C₁₋₆)alkylamino, arylamino, C₂₋₆ alkylcarbonylamino, C₁₋₆alkylsulfonylamino, formyl, C₂₋₆ alkylcarbonyl, C₃₋₆ cycloalkylcarbonyl,C₃₋₆ heterocycloalkylcarbonyl, carboxy, C₂₋₆ alkoxycarbonyl,aminocarbonyl, C₁₋₆ alkylaminocarbonyl, di(C₁₋₆)alkylaminocarbonyl,aminosulfonyl, C₁₋₆ alkylaminosulfonyl and di(C₁₋₆)alkylaminosulfonyl.

Suitable examples of optional substituents on the moiety Y includehalogen, C₁₋₆ alkyl and difluoromethoxy.

Typical examples of optional substituents on the moiety Y includehalogen and C₁₋₆ alkyl.

Examples of particular substituents on the moiety Y include fluoro,chloro, bromo, cyano, nitro, methyl, isopropyl, trifluoromethyl,hydroxy, methoxy, difluoromethoxy, trifluoromethoxy, methylthio,methylsulfinyl, methylsulfonyl, methylsulfonyloxy, amino, methylamino,tert-butylamino, dimethylamino, phenylamino, acetylamino,methylsulfonylamino, formyl, acetyl, cyclopropylcarbonyl,azetidinylcarbonyl, pyrrolidinylcarbonyl, piperidinylcarbonyl,piperazinylcarbonyl, morpholinylcarbonyl, carboxy, methoxycarbonyl,aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl,aminosulfonyl, methylaminosulfonyl and dimethylaminosulfonyl.

Suitable examples of particular substituents on the moiety Y includefluoro, chloro, bromo, methyl and difluoromethoxy.

Typical examples of particular substituents on the moiety Y includechloro and methyl.

Typical values of Y include benzocyclobutenyl, phenyl, fluorophenyl(including 2-fluorophenyl, 3-fluorophenyl and 4-fluorophenyl),chlorophenyl (including 2-chlorophenyl, 3-chlorophenyl and4-chlorophenyl), difluorophenyl (including 2,6-difluorophenyl),(chloro)(fluoro)phenyl (including 5-chloro-2-fluorophenyl and2-chloro-5-fluorophenyl), dichlorophenyl (including 2,5-dichlorophenyland 2,6-dichlorophenyl), methylphenyl (including 4-methylphenyl),dimethylphenyl (including 2,5-dimethylphenyl and 2,6-dimethylphenyl),(trifluoromethyl)phenyl [including 2-(trifluoromethyl)phenyl],(chloro)(trifluoromethyl)phenyl [including5-chloro-2-(trifluoromethyl)phenyl], (methyl)-(trifluoromethyl)phenyl[including 2-methyl-5-(trifluoromethyl)phenyl],bis(trifluoromethyl)phenyl [including 2,5-bis(trifluoromethyl)phenyl],methoxyphenyl (including 2-methoxyphenyl), (difluoromethoxy)phenyl[including 2-(difluoromethoxy)phenyl and 3-(difluoromethoxy)phenyl],(difluoromethoxy)(fluoro)phenyl [including2-(difluoromethoxy)-5-fluorophenyl and2-(difluoromethoxy)-6-fluorophenyl], (chloro)(difluoromethoxy)phenyl[including 5-chloro-2-(difluoromethoxy)phenyl and6-chloro-2-(difluoromethoxy)phenyl], (cyano)(difluoromethoxy)phenyl[including 6-cyano-2-(difluoromethoxy)phenyl], (trifluoromethoxy)phenyl[including 2-(trifluoromethoxy)-phenyl], methylsulfonyloxyphenyl,(amino)(chloro)phenyl (including 5-amino-2-chlorophenyl), methylthienyl(including 3-methylthien-2-yl), methylthiazolyl (including2-methyl-1,3-thiazol-4-yl), (chloro)(methyl)thiazolyl (including5-chloro-2-methyl-1,3-thiazol-4-yl), dimethylthiazolyl (including2,4-dimethyl-1,3-thiazol-5-yl) and pyridinyl (including pyridin-3-yl andpyridin-4-yl). Additional values include (bromo)(difluoromethoxy)phenyl[including 6-bromo-2-(difluoromethoxy)phenyl] and(bromo)(difluoromethoxy)(fluoro)phenyl [including5-bromo-2-(difluoromethoxy)-6-fluorophenyl].

Selected values of Y include phenyl, dichlorophenyl, dimethylphenyl,(difluoromethoxy)phenyl, (difluoromethoxy)(fluoro)phenyl,methylsulfonyloxyphenyl, methylthienyl and dimethylthiazolyl.

Illustrative values of Y include phenyl, dichlorophenyl, dimethylphenyl,(difluoromethoxy)phenyl, (difluoromethoxy)(fluoro)phenyl,(bromo)(difluoromethoxy)-phenyl and(bromo)(difluoromethoxy)(fluoro)phenyl.

Suitable values of Y include phenyl, dichlorophenyl and dimethylphenyl.

In one embodiment, Y represents phenyl.

In another embodiment, Y represents 2,5-dichlorophenyl.

In another embodiment, Y represents 2,5-dimethylphenyl.

In a particular embodiment, Y represents 2-(difluoromethoxy)phenyl.

In another embodiment, Y represents (difluoromethoxy)(fluoro)phenyl.

In another embodiment, Y represents (bromo)(difluoromethoxy)phenyl.

In another embodiment, Y represents(bromo)(difluoromethoxy)(fluoro)phenyl.

In another embodiment, Y represents 3-methylthien-2-yl.

In another embodiment, Y represents 2,4-dimethyl-1,3-thiazol-5-yl.

In one embodiment, Z represents hydrogen.

In another embodiment, Z is other than hydrogen.

In a selected embodiment, Z represents hydrogen; or Z represents C₁₋₆alkyl, C₃₋₇ cycloalkyl, aryl, C₃₋₇ heterocycloalkyl, C₃₋₇heterocycloalkenyl or heteroaryl, any of which groups may be optionallysubstituted by one or more substituents; or Z represents —Z¹—Z² or—Z¹—C(O)—Z², either of which moieties may be optionally substituted byone or more substituents.

In a further embodiment, Z represents C₁₋₆ alkyl, C₃₋₇ cycloalkyl, aryl,C₃₋₇ heterocycloalkyl, C₃₋₇ heterocycloalkenyl or heteroaryl, any ofwhich groups may be optionally substituted by one or more substituents;or Z represents —Z¹—Z² or —Z¹—C(O)—Z², either of which moieties may beoptionally substituted by one or more substituents.

Suitably, Z represents hydrogen; or Z represents C₁₋₆ alkyl, aryl orheteroaryl, any of which groups may be optionally substituted by one ormore substituents; or Z represents —Z¹—Z², which moiety may beoptionally substituted by one or more substituents.

Appropriately, Z represents hydrogen; or Z represents C₁₋₆ alkyl, arylor heteroaryl, any of which groups may be optionally substituted by oneor more substituents.

Typically, Z represents hydrogen, fluoro or trifluoromethyl; or Zrepresents methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl,isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,phenyl, tetrahydrofuranyl, pyrrolidinyl, indolinyl, tetrahydropyranyl,piperidinyl, 1,2,3,4-tetrahydroquinolinyl, morpholinyl, azocanyl,thiazolinyl, furyl, thienyl, pyrazolyl, 4,5,6,7-tetrahydroindazolyl,benzoxazolyl, isoxazolyl, thiazolyl, benzothiazolyl, imidazolyl,benzimidazolyl, [1,2,4]triazolo[1,5-c]-pyrimidinyl, tetrazolyl,pyridinyl, quinolinyl, isoquinolinyl, phthalazinyl, pyrimidinyl orpyrazinyl, any of which groups may be optionally substituted by one ormore substituents; or Z represents —Z¹—Z² or —Z¹—C(O)—Z², either ofwhich moieties may be optionally substituted by one or moresubstituents.

Appositely, Z represents hydrogen; or Z represents methyl, phenyl orpyridinyl, any of which groups may be optionally substituted by one ormore substituents.

The moiety Z′ represents a divalent radical derived from an aryl, C₃₋₇heterocycloalkyl or heteroaryl group, any of which groups may beoptionally substituted by one or more substituents. Typically, themoiety Z′ represents a divalent radical derived from a phenyl,pyrrolidinyl, piperazinyl, pyrazolyl, thiazolyl, triazolyl, tetrazolylor pyridinyl group, any of which groups may be optionally substituted byone or more substituents. Typical values of the moiety Z′ include thegroups of formula (Za), (Zb), (Zc), (Zd), (Ze), (Zf), (Zg), (Zh), (Zj)and (Zk):

wherein

the symbols # represent the points of attachment of the moiety Z¹ to theremainder of the molecule; and

the asterisks (*) represent the site of attachment of optionalsubstituents.

Particular values of the moiety Z¹ include the groups of formula (Za),(Zc), (Ze), (Zf), (Zg), (Zh) and (Zj) as depicted above.

The moiety Z² represents aryl, C₃₋₇ heterocycloalkyl, C₃₋₇heterocycloalkenyl or heteroaryl, any of which groups may be optionallysubstituted by one or more substituents. Typically, Z² representsphenyl, pyrrolidinyl, oxazolidinyl, imidazolidinyl, morpholinyl,imidazolinyl, thiazolyl, imidazolyl, tetrazolyl or pyridinyl, any ofwhich groups may be optionally substituted by one or more substituents.

Examples of optional substituents which may be present on the moiety Z,Z¹ or Z² include one, two or three substituents independently selectedfrom halogen, cyano, nitro, C₁₋₆ alkyl, trifluoromethyl, oxo, hydroxy,hydroxy(C₁₋₆)alkyl, C₁₋₆ alkoxy, difluoromethoxy, trifluoromethoxy, C₁₋₃alkylenedioxy, C₁₋₆ alkylthio, C₁₋₆ alkylsulfinyl, C₁₋₆ alkylsulfonyl,amino, C₁₋₆ alkylamino, di(C₁₋₆)alkylamino,di(C₁₋₆)alkylamino(C₁₋₆)alkyl, C₂₋₆ alkylcarbonylamino, C₁₋₆alkylsulfonylamino, formyl, C₂₋₆ alkylcarbonyl, carboxy, C₂₋₆alkoxycarbonyl, aminocarbonyl, C₁₋₆ alkylaminocarbonyl,di(C₁₋₆)alkylaminocarbonyl, aminosulfonyl, C₁₋₆ alkylaminosulfonyl,di(C₁₋₆)alkylaminosulfonyl, aminocarbonylamino and hydrazinocarbonyl.

Examples of particular substituents on the moiety Z, Z¹ or Z² includefluoro, chloro, bromo, cyano, nitro, methyl, ethyl, isopropyl,trifluoromethyl, oxo, hydroxy, hydroxymethyl, methoxy, difluoromethoxy,trifluoromethoxy, methylenedioxy, methylthio, methylsulfinyl,methylsulfonyl, amino, methylamino, tert-butylamino, dimethylamino,dimethylaminomethyl, dimethylaminoethyl, acetylamino,methylsulfonylamino, formyl, acetyl, carboxy, methoxycarbonyl,tert-butoxycarbonyl, aminocarbonyl, methylaminocarbonyl,dimethylaminocarbonyl, aminosulfonyl, methylaminosulfonyl,dimethylaminosulfonyl, aminocarbonylamino and hydrazinocarbonyl.

Typical values of Z² include phenyl, hydroxyphenyl, oxopyrrolidinyl,dioxo-pyrrolidinyl, (hydroxy)(oxo)pyrrolidinyl,(amino)(oxo)pyrrolidinyl, (oxo)oxazolidinyl, oxoimidazolidinyl,morpholinyl, imidazolinyl, methylthiazolyl, formylthiazolyl, imidazolyl,tetrazolyl and pyridinyl.

Selected values of Z² include oxopyrrolidinyl and (oxo)oxazolidinyl. Inone embodiment, Z² represents oxopyrrolidinyl. In another embodiment, Z²represents (oxo)oxazolidinyl.

Typical values of Z include hydrogen, fluoro, trifluoromethyl, methyl,ethyl, n-propyl, isopropyl, isobutyl, tert-butyl, cyclopropyl,cyclopentyl, cyclohexyl, oxo-cyclohexyl, phenyl, bromophenyl,cyanophenyl, nitrophenyl, methoxyphenyl, difluoromethoxyphenyl,trifluoromethoxyphenyl, methylenedioxyphenyl, methylsulfonylphenyl,dimethylaminophenyl, acetylaminophenyl, methylsulfonylaminophenyl,carboxyphenyl, aminocarbonylphenyl, methylaminocarbonylphenyl,dimethylaminocarbonylphenyl, aminocarbonylaminophenyl,tetrahydrofuranyl, oxopyrrolidinyl, dimethylamino-pyrrolidinyl,tert-butoxycarbonylpyrrolidinyl, indolinyl, tetrahydropyranyl,piperidinyl, ethylpiperidinyl, tert-butoxycarbonylpiperidinyl,aminocarbonylpiperidinyl, 2-oxo-3,4-dihydroquinolinyl, morpholinyl,azocanyl, oxothiazolinyl, furyl, hydroxymethylfuryl, thienyl,methylpyrazolyl, dimethylpyrazolyl, 4,5,6,7-tetrahydroindazolyl,benzoxazolyl, methylisoxazolyl, dimethylisoxazolyl, methylthiazolyl,aminothiazolyl, benzothiazolyl, methylbenzothiazolyl,aminobenzothiazolyl, imidazolyl, methylimidazolyl,methyl-benzimidazolyl, dimethyl[1,2,4]triazolo[1,5-c]pyrimidinyl,dimethylaminoethyltetrazolyl, pyridinyl, fluoropyridinyl,chloropyridinyl, cyanopyridinyl, methylpyridinyl,(cyano)-(methyl)pyridinyl, trifluoromethylpyridinyl, oxopyridinyl,methoxypyridinyl, methylsulfonylpyridinyl, dimethylaminomethylpyridinyl,acetylaminopyridinyl, carboxypyridinyl, methoxycarbonylpyridinyl,aminocarbonylpyridinyl, (aminocarbonyl)(fluoro)-pyridinyl,methylaminocarbonylpyridinyl, dimethylaminocarbonylpyridinyl,hydrazino-carbonylpyridinyl, quinolinyl, isoquinolinyl,(methyl)(oxo)phthalazinyl, pyrimidinyl, pyrazinyl,oxopyrrolidinylphenyl, dioxopyrrolidinylphenyl,(hydroxy)(oxo)pyrrolidinylphenyl, (amino)(oxo)pyrrolidinylphenyl,(oxo)oxazolidinylphenyl, oxoimidazolidinyl-phenyl, imidazolinylphenyl,methylthiazolylphenyl, formylthiazolylphenyl, imidazolyl-phenyl,tetrazolylphenyl, phenylpyrrolidinyl, hydroxyphenylpiperazinyl,(methyl)-(phenyl)pyrazolyl, oxoimidazolidinylthiazolyl,hydroxyphenyltriazolyl, morpholinyl-tetrazolyl,oxopyrrolidinylpyridinyl, (oxo)oxazolidinylpyridinyl,oxoimidazolidinyl-pyridinyl, pyridinylthiazolyl, pyridinyltetrazolyl andmorpholinylcarbonylphenyl.

Particular values of Z include hydrogen, methyl, phenyl,methylsulfonylphenyl, aminocarbonylphenyl, pyridinyl,methylsulfonylpyridinyl, aminocarbonylpyridinyl, oxopyrrolidinylphenyl,(hydroxy)(oxo)pyrrolidinylphenyl and (oxo)oxazolidinylphenyl.

Suitable values of Z include hydrogen, methyl, phenyl,aminocarbonylphenyl and aminocarbonylpyridinyl.

In a first embodiment, Z represents hydrogen. In a second embodiment, Zrepresents methyl. In a third embodiment, Z represents phenyl. In afourth embodiment, Z represents methylsulfonylphenyl. In one aspect ofthat embodiment, Z represents 3-(methylsulfonyl)phenyl. In anotheraspect of that embodiment, Z represents 4-(methyl-sulfonyl)phenyl. In afifth embodiment, Z represents aminocarbonylphenyl. In one aspect ofthat embodiment, Z represents 4-(aminocarbonyl)phenyl. In a sixthembodiment, Z represents pyridinyl. In one aspect of that embodiment, Zrepresents pyridin-4-yl. In a seventh embodiment, Z representsaminocarbonylpyridinyl. In one aspect of that embodiment, Z represents6-(aminocarbonyl)pyridin-3-yl. In an eighth embodiment, Z representsoxopyrrolidinylphenyl. In one aspect of that embodiment, Z represents3-(2-oxopyrrolidin-1-yl)phenyl. In a ninth embodiment, Z represents(hydroxy)(oxo)pyrrolidinylphenyl. In one aspect of that embodiment, Zrepresents 3-(3-hydroxy-2-oxopyrrolidin-1-yl)phenyl. In another aspectof that embodiment, Z represents3-(4-hydroxy-2-oxopyrrolidin-1-yl)phenyl. In a tenth embodiment, Zrepresents (oxo)oxazolidinylphenyl. In one aspect of that embodiment, Zrepresents 3-(2-oxo-oxazolidinyl-3-yl)phenyl. In an eleventh embodiment,Z represents methylsulfonylpyridinyl.

Suitably, R¹, R² or R³ independently represent hydrogen, halogen, cyano,trifluoromethyl, —OR^(a) or —CO₂R^(d); or C₁₋₆ alkyl, C₂₋₆ alkynyl,aryl, C₃₋₇ heterocycloalkyl, C₃₋₇ heterocycloalkenyl, heteroaryl,(C₃₋₇)heterocycloalkyl(C₁₋₆)alkyl-aryl-,heteroaryl-(C₃₋₇)heterocycloalkyl-, (C₃₋₇)cycloalkyl-heteroaryl-,(C₃₋₇)cycloalkyl(C₁₋₆)alkyl-heteroaryl-, (C₄₋₇)cycloalkenyl-heteroaryl-,(C₄₋₉)bicycloalkyl-heteroaryl-, (C₃₋₇)heterocycloalkyl-heteroaryl-,(C₃₋₇)hetero cyclo alkyl(C₁₋₆)alkyl-hetero aryl-,(C₃₋₇)heterocycloalkenyl-heteroaryl-,(C₄₋₉)heterobicycloalkyl-heteroaryl- or(C₄₋₉)spiroheterocycloalkyl-heteroaryl-, any of which groups may beoptionally substituted by one or more substituents.

Examples of optional substituents which may be present on R¹, R² or R³include one, two or three substituents independently selected fromhalogen, halo(C₁₋₆)alkyl, cyano, cyano(C₁₋₆)alkyl, nitro,nitro(C₁₋₆)alkyl, C₁₋₆ alkyl, difluoromethyl, trifluoromethyl,difluoroethyl, trifluoroethyl, C₂₋₆ alkenyl, hydroxy,hydroxy(C₁₋₆)alkyl, C₁₋₆ alkoxy, difluoromethoxy, trifluoromethoxy,trifluoroethoxy, carboxy(C₃₋₇)cycloalkyloxy, C₁₋₃ alkylenedioxy, C₁₋₆alkoxy(C₁₋₆)alkyl, C₁₋₆ alkylthio, C₁₋₆ alkylsulphinyl, C₁₋₆alkylsulphonyl, (C₁₋₆)alkylsulphonyl(C₁₋₆)alkyl, oxo, amino,amino(C₁₋₆)alkyl, C₁₋₆ alkylamino, di(C₁₋₆)alkylamino,hydroxy(C₁₋₆)alkylamino, C₁₋₆ alkoxyamino, (C₁₋₆)alkoxy(C₁₋₆)alkylamino,[(C₁₋₆)alkoxy](hydroxy)(C₁₋₆)alkylamino,[(C₁₋₆)alkylthio](hydroxy)(C₁₋₆)alkylamino,N—[(C₁₋₆)alkyl]-N-[hydroxy(C₁₋₆)alkyl]amino,di(C₁₋₆)alkylamino(C₁₋₆)alkylamino,N-[di(C₁₋₆)alkylamino(C₁₋₆)alkyl]-N-[hydroxy(C₁₋₆)alkyl]amino,hydroxy(C₁₋₆)alkyl-(C₃₋₇)cycloalkylamino,(hydroxy)[(C₃₋₇)cycloalkyl(C₁₋₆)alkyl]amino,(C₃₋₇)heterocycloalkyl(C₁₋₆)alkylamino,oxo(C₃₋₇)heterocycloalkyl(C₁₋₆)alkylamino, (C₁₋₆)alkylheteroarylamino,heteroaryl(C₁₋₆)alkylamino, (C₁₋₆)alkylhetero aryl(C₁₋₆)alkylamino, C₂₋₆alkylcarbonylamino, N—[(C₁₋₆)alkyl]-N—[(C₂₋₆)alkylcarbonyl]amino,(C₂₋₆)alkylcarbonylamino(C₁₋₆)alkyl, C₃₋₆ alkenylcarbonylamino,bis[(C₃₋₆)alkenylcarbonyl]amino,N—[(C₁₋₆)alkyl]-N—[(C₃₋₇)cycloalkylcarbonyl]amino, C₂₋₆alkoxycarbonylamino, C₂₋₆ alkoxycarbonyl(C₁₋₆)alkylamino, C₁₋₆alkylaminocarbonylamino, C₁₋₆ alkylsulphonylamino,N—[(C₁₋₆)alkyl]-N—[(C₁₋₆)alkylsulphonyl]amino,bis[(C₁₋₆)alkylsulphonyl]amino,N—[(C₁₋₆)alkyl]-N-[carboxy(C₁₋₆)alkyl]amino,carboxy(C₃₋₇)cycloalkylamino, carboxy-(C₃₋₇)cycloalkyl(C₁₋₆)alkylamino,formyl, C₂₋₆ alkylcarbonyl, (C₃₋₇)cycloalkylcarbonyl, phenylcarbonyl,(C₂₋₆)alkylcarbonyloxy(C₁₋₆)alkyl, carboxy, carboxy(C₁₋₆)alkyl, C₂₋₆alkoxycarbonyl, C₂₋₆ alkoxycarbonyl(C₁₋₆)alkyl,morpholinyl(C₁₋₆)alkoxycarbonyl, C₂₋₆ alkoxycarbonylmethylidenyl, acarboxylic acid isostere or prodrug moiety Ω, —(C₁₋₆)alkyl-Ω,aminocarbonyl, C₁₋₆ alkylaminocarbonyl, hydroxy(C₁₋₆)alkylaminocarbonyl,di(C₁₋₆)alkylaminocarbonyl, aminocarbonyl(C₁₋₆)alkyl, aminosulphonyl,di(C₁₋₆)alkylamino-sulphonyl, (C₁₋₆)alkylsulphoximinyl and[(C₁₋₆)alkyl][N—(C₁₋₆)alkyl]-sulphoximinyl.

By the expression “carboxylic acid isostere or prodrug moiety” is meantany functional group, structurally distinct from a carboxylic acidmoiety, that will be recognised by a biological system as being similarto, and thus capable of mimicking, a carboxylic acid moiety, or will bereadily convertible by a biological system in vivo into a carboxylicacid moiety. A synopsis of some common carboxylic acid isosteres ispresented by N. A. Meanwell in J. Med. Chem., 2011, 54, 2529-2591 (cf.in particular Figures 25 and 26). An alternative carboxylic acidisostere is described by N Pemberton et al. in ACS Med. Chem. Lett.,2012, 3, 574-578. Typical examples of suitable carboxylic acid isostereor prodrug moieties represented by Ω include the functional groups offormula (i) to (xliii):

wherein

the asterisk (*) represents the site of attachment to the remainder ofthe molecule;

n is zero, 1 or 2;

X represents oxygen or sulphur;

R^(f) represents hydrogen, C₁₋₆ alkyl or —CH₂CH(OH)CH₂OH;

R^(g) represents C₁₋₆ alkyl, trifluoromethyl, —CH₂CH₂F, —CH₂CHF₂,—CH₂CF₃ or —CF₂CF₃;

R^(h) represents hydrogen, cyano or —CO₂R^(d), in which R^(d) is asdefined above; and

R^(j) represents hydrogen or halogen.

In one embodiment, n is zero. In another embodiment, n is 1. In afurther embodiment, n is 2.

In one embodiment, X represents oxygen. In another embodiment, Xrepresents sulphur.

In one embodiment, R^(f) represents hydrogen. In another embodiment,R^(f) represents C₁₋₆ alkyl, especially methyl. In a further embodiment,R^(f) is —CH₂CH(OH)CH₂OH.

In one embodiment, R^(g) represents C₁₋₆ alkyl, especially methyl. Inanother embodiment, R^(g) represents trifluoromethyl, —CH₂CH₂F,—CH₂CHF₂, —CH₂CF₃ or —CF₂CF₃. In a first aspect of that embodiment,R^(g) represents trifluoromethyl. In a second aspect of that embodiment,R^(g) represents —CH₂CH₂F. In a third aspect of that embodiment, R^(g)represents —CH₂CHF₂. In a fourth aspect of that embodiment, R^(g)represents —CH₂CF₃. In a fifth aspect of that embodiment, R^(g)represents —CF₂CF₃.

In one embodiment, R^(h) is hydrogen. In another embodiment, R^(h)represents cyano. In a further embodiment, R^(h) represents —CO₂R^(d),especially methoxycarbonyl.

In one embodiment, R^(j) represents hydrogen. In another embodiment,R^(j) represents halogen, especially chloro.

In a selected embodiment, Ω represents tetrazolyl, especially a C-linkedtetrazolyl moiety of formula (xxiv) or (xxv) as depicted above, inparticular a group of formula (xxiv) as depicted above.

In another embodiment, Ω represents C₁₋₆ alkylsulphonylaminocarbonyl,i.e. a moiety of formula (iii) as depicted above wherein R^(g)represents C₁₋₆ alkyl.

In another embodiment, Ω represents C₁₋₆ alkylamino-sulphonyl, i.e. amoiety of formula (x) as depicted above wherein R^(g) represents C₁₋₆alkyl.

In a further embodiment, Ω represents (C₁₋₆)alkylcarbonylaminosulphonyl,i.e. a moiety of formula (v) as depicted above wherein R^(g) representsC₁₋₆ alkyl.

Typical examples of optional substituents on R¹, R² or R³ include one,two or three substituents independently selected from C₁₋₆ alkyl,hydroxy, hydroxy(C₁₋₆)alkyl and (C₁₋₆)alkylsulphoximinyl.

Suitable examples of optional substituents on R¹, R² or R³ include one,two or three substituents independently selected from C₁₋₆ alkyl.

Examples of particular substituents on R¹, R² or R³ include fluoro,chloro, bromo, fluoromethyl, fluoroisopropyl, cyano, cyanoethyl, nitro,nitromethyl, methyl, ethyl, isopropyl, isobutyl, tert-butyl,difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, ethenyl,hydroxy, hydroxymethyl, hydroxyisopropyl, methoxy, isopropoxy,difluoromethoxy, trifluoromethoxy, trifluoroethoxy,carboxycyclobutyloxy, methylenedioxy, ethylenedioxy, methoxymethyl,methoxyethyl, methylthio, methylsulphinyl, methylsulphonyl,methylsulphonylethyl, oxo, amino, aminomethyl, aminoisopropyl,methylamino, ethylamino, dimethylamino, hydroxyethylamino,hydroxypropylamino, (hydroxy)(methyl)propylamino, methoxyamino,methoxyethylamino, (hydroxy)-(methoxy)(methyl)propylamino,(hydroxy)(methylthio)butylamino, N-(hydroxyethyl)-N-(methyl)amino,dimethylaminoethylamino, (dimethylamino)(methyl)propylamino,N-(dimethylaminoethyl)-N-(hydroxyethyl)amino,hydroxymethylcyclopentylamino, hydroxycyclobutylmethylamino,(cyclopropyl)(hydroxy)propylamino, morpholinylethyl-amino,oxopyrrolidinylmethylamino, ethyloxadiazolylamino,methylthiadiazolylamino, thiazolylmethylamino, thiazolylethylamino,pyrimidinylmethylamino, methylpyrazolyl-methylamino, acetylamino,N-acetyl-N-methylamino, N-isopropylcarbonyl-N-methylamino,acetylaminomethyl, ethenylcarbonylamino, bis(ethenylcarbonyl)amino,N-cyclopropylcarbonyl-N-methylamino, methoxycarbonylamino,ethoxycarbonylamino, tert-butoxycarbonylamino,methoxycarbonylethylamino, ethylaminocarbonylamino,butylaminocarbonylamino, methylsulphonylamino,N-methyl-N-(methylsulphonyl)amino, bis(methylsulphonyl)amino,N-(carboxymethyl)-N-methylamino, N-(carboxyethyl)-N-methylamino,carboxycyclopentylamino, carboxycyclopropylmethylamino, formyl, acetyl,isopropylcarbonyl, cyclobutylcarbonyl, phenylcarbonyl, acetoxyisopropyl,carboxy, carboxymethyl, carboxyethyl, methoxycarbonyl, ethoxycarbonyl,n-butoxycarbonyl, tert-butoxycarbonyl, methoxycarbonylmethyl,ethoxycarbonylmethyl, ethoxycarbonylethyl, morpholinylethoxycarbonyl,ethoxycarbonylmethylidenyl, methylsulphonylaminocarbonyl,acetylaminosulphonyl, methoxyaminocarbonyl, tetrazolyl,tetrazolylmethyl, hydroxyoxadiazolyl, aminocarbonyl,methylaminocarbonyl, hydroxyethylaminocarbonyl, dimethylaminocarbonyl,aminocarbonylmethyl, aminosulphonyl, methylaminosulphonyl,dimethylaminosulphonyl, methylsulphoximinyl and(methyl)(N-methyl)sulphoximinyl.

Typical examples of particular substituents on R¹, R² or R³ include one,two or three substituents independently selected from methyl, hydroxy,hydroxyisopropyl and methylsulphoximinyl.

Suitable examples of particular substituents on R¹, R² or R³ includeone, two or three substituents independently selected from methyl.

Typically, R¹ represents hydrogen, halogen, cyano, —OR^(a) or —CO₂R^(d);or C₁₋₆ alkyl, C₂₋₆ alkynyl, aryl, C₃₋₇ heterocycloalkyl, C₃₋₇heterocycloalkenyl, heteroaryl, (C₃₋₇)heterocycloalkyl(C₁₋₆)alkyl-aryl-,heteroaryl(C₃₋₇)heterocycloalkyl-, (C₃₋₇)cycloalkyl-heteroaryl-,(C₃₋₇)cyclo alkyl(C₁₋₆)alkyl-hetero aryl-,(C₄₋₇)cycloalkenyl-heteroaryl-, (C₄₋₉)bicycloalkyl-heteroaryl-,(C₃₋₇)heterocycloalkyl-heteroaryl-, (C₃₋₇)hetero cycloalkyl(C₁₋₆)alkyl-hetero aryl-, (C₃₋₇)hetero cyclo alkenyl-hetero aryl-,(C₄₋₉)heterobicycloalkyl-heteroaryl- or(C₄₋₉)spiroheterocycloalkyl-heteroaryl-, any of which groups may beoptionally substituted by one or more substituents.

Suitably, R¹ represents halogen, cyano, —OR^(a) or —CO₂R^(d); or C₁₋₆alkyl, C₂₋₆ alkynyl, aryl, C₃₋₇ heterocycloalkyl, C₃₋₇heterocycloalkenyl, heteroaryl, (C₃₋₇)heterocycloalkyl(C₁₋₆)alkyl-aryl-,heteroaryl(C₃₋₇)heterocycloalkyl-, (C₃₋₇)cycloalkyl-heteroaryl-,(C₃₋₇)cycloalkyl(C₁₋₆)alkyl-heteroaryl-, (C₄₋₇)cycloalkenyl-heteroaryl-,(C₄₋₉)bicycloalkyl-heteroaryl-, (C₃₋₇)heterocycloalkyl-heteroaryl-,(C₃₋₇)hetero cyclo alkyl(C₁₋₆)alkyl-hetero aryl-, (C₃₋₇)hetero cycloalkenyl-hetero aryl-, (C₄₋₉)heterobicycloalkyl-heteroaryl- or(C₄₋₉)spiroheterocycloalkyl-heteroaryl-, any of which groups may beoptionally substituted by one or more substituents.

Generally, R¹ represents halogen, cyano or —OR^(a); or C₁₋₆ alkyl, C₂₋₆alkynyl, aryl, C₃₋₇ heterocycloalkyl, C₃₋₇ heterocycloalkenyl,heteroaryl, (C₃₋₇)heterocycloalkyl-(C₁₋₆)alkyl-aryl-, heteroaryl(C₃₋₇)hetero cyclo alkyl-, (C₃₋₇)cycloalkyl-heteroaryl-, (C₃₋₇)cycloalkyl(C₁₋₆)alkyl-hetero aryl-, (C₄₋₇)cycloalkenyl-heteroaryl-,(C₄₋₉)bicyclo alkyl-heteroaryl-, (C₃₋₇)hetero cyclo alkyl-hetero aryl-,(C₃₋₇)heterocycloalkyl(C₁₋₆)alkyl-heteroaryl-,(C₃₋₇)heterocycloalkenyl-heteroaryl-,(C₄₋₉)heterobicycloalkyl-heteroaryl- or(C₄₋₉)spiroheterocycloalkyl-heteroaryl-, any of which groups may beoptionally substituted by one or more substituents.

More typically, R¹ represents hydrogen, halogen or —OR^(a); or R¹represents heteroaryl or (C₃₋₇)cycloalkyl-heteroaryl-, either of whichgroups may be optionally substituted by one or more substituents.

More generally, R¹ represents hydrogen, halogen or —OR^(a); or R¹represents heteroaryl, which group may be optionally substituted by oneor more substituents.

In a first embodiment, R¹ represents hydrogen.

In a second embodiment, R¹ represents halogen. In one aspect of thatembodiment, R¹ represents bromo. In another aspect of that embodiment,R¹ represents chloro.

In a third embodiment, R¹ represents —OR^(a).

In a fourth embodiment, R¹ represents —CO₂Rd.

In a fifth embodiment, R¹ represents optionally substituted C₁₋₆ alkyl.In one aspect of that embodiment, R¹ represents optionally substitutedethyl.

In a sixth embodiment, R¹ represents optionally substituted C₂₋₆alkynyl. In one aspect of that embodiment, R¹ represents optionallysubstituted butyryl.

In a seventh embodiment, R¹ represents optionally substituted aryl. Inone aspect of that embodiment, R¹ represents optionally substitutedphenyl.

In an eighth embodiment, R¹ represents optionally substituted C₃₋₇heterocycloalkyl.

In a ninth embodiment, R¹ represents optionally substituted C₃₋₇heterocycloalkenyl.

In a tenth embodiment, R¹ represents optionally substituted heteroaryl.In selected aspects of that embodiment, R¹ represents benzofuryl,thienyl, indolyl, pyrazolyl, indazolyl, isoxazolyl, thiazolyl,imidazolyl, pyridinyl, quinolinyl, pyridazinyl, pyrimidinyl orpyrazinyl, any of which groups may be optionally substituted by one ormore substituents.

In an eleventh embodiment, R¹ represents optionally substituted(C₃₋₇)-heterocycloalkyl(C₁₋₆)alkyl-aryl-. In a first aspect of thatembodiment, R¹ represents optionally substitutedpyrrolidinylmethylphenyl-. In a second aspect of that embodiment, R¹represents optionally substituted piperazinylmethylphenyl-.

In a twelfth embodiment, R¹ represents optionally substitutedheteroaryl(C₃₋₇)-heterocycloalkyl-. In one aspect of that embodiment, R¹represents optionally substituted pyridinylpiperazinyl-.

In a thirteenth embodiment, R¹ represents optionally substituted(C₃₋₇)cycloalkyl-heteroaryl-. In a first aspect of that embodiment, R¹represents optionally substituted cyclohexylpyrazolyl-. In a secondaspect of that embodiment, R¹ represents optionally substitutedcyclohexylpyridinyl-. In a third aspect of that embodiment, R¹represents optionally substituted cyclopropylpyrimidinyl-. In a fourthaspect of that embodiment, R¹ represents optionally substitutedcyclobutylpyrimidinyl-. In a fifth aspect of that embodiment, R¹represents optionally substituted cyclopentylpyrimidinyl-. In a sixthaspect of that embodiment, R¹ represents optionally substitutedcyclohexylpyrimidinyl-. In a seventh aspect of that embodiment, R¹represents optionally substituted cyclohexylpyrazinyl-.

In a fourteenth embodiment, R¹ represents optionally substituted(C₄₋₇)-cycloalkenyl-heteroaryl-.

In a fifteenth embodiment, R¹ represents optionally substituted(C₃₋₇)-heterocycloalkyl-heteroaryl-. In a first aspect of thatembodiment, R¹ represents optionally substituted pyrrolidinylpyridinyl-.In a second aspect of that embodiment, R¹ represents optionallysubstituted tetrahydropyranylpyridinyl-. In a third aspect of thatembodiment, R¹ represents optionally substituted piperidinylpyridinyl-.In a fourth aspect of that embodiment, R¹ represents optionallysubstituted piperazinylpyridinyl-. In a fifth aspect of that embodiment,R¹ represents optionally substituted morpholinylpyridinyl-. In a sixthaspect of that embodiment, R¹ represents optionally substitutedthiomorpholinylpyridinyl-. In a seventh aspect of that embodiment, R¹represents optionally substituted diazepanylpyridinyl-. In an eighthaspect of that embodiment, R¹ represents optionally substitutedoxetanylpyrimidinyl-. In a ninth aspect of that embodiment, R¹represents optionally substituted azetidinylpyrimidinyl-. In a tenthaspect of that embodiment, R¹ represents optionally substitutedtetrahydrofuranylpyrimidinyl-. In an eleventh aspect of that embodiment,R¹ represents optionally substituted pyrrolidinylpyrimidinyl-. In atwelfth aspect of that embodiment, R¹ represents optionally substitutedtetrahydropyranylpyrimidinyl-. In a thirteenth aspect of thatembodiment, R¹ represents optionally substitutedpiperidinylpyrimidinyl-. In a fourteenth aspect of that embodiment, R¹represents optionally substituted piperazinylpyrimidinyl-. In afifteenth aspect of that embodiment, R¹ represents optionallysubstituted morpholinylpyrimidinyl-. In a sixteenth aspect of thatembodiment, R¹ represents optionally substitutedthiomorpholinylpyrimidinyl-. In a seventeenth aspect of that embodiment,R¹ represents optionally substituted azepanylpyrimidinyl-. In aneighteenth aspect of that embodiment, R¹ represents optionallysubstituted oxazepanylpyrimidinyl-. In a nineteenth aspect of thatembodiment, R¹ represents optionally substituted diazepanylpyrimidinyl-.In a twentieth aspect of that embodiment, R¹ represents optionallysubstituted thiadiazepanylpyrimidinyl-. In a twenty-first aspect of thatembodiment, R¹ represents optionally substituted oxetanylpyrazinyl-. Ina twenty-second aspect of that embodiment, R¹ represents optionallysubstituted piperidinylpyrazinyl-.

In a sixteenth embodiment, R¹ represents optionally substituted(C₃₋₇)-heterocycloalkyl(C₁₋₆)alkyl-heteroaryl-. In a first aspect ofthat embodiment, R¹ represents optionally substitutedmorpholinylmethylthienyl-. In a second aspect of that embodiment, R¹represents optionally substituted morpholinylethylpyrazolyl-.

In a seventeenth embodiment, R¹ represents optionally substituted(C₃₋₇)-heterocycloalkenyl-heteroaryl-.

In an eighteenth embodiment, R¹ represents optionally substituted(C₄₋₉)-heterobicycloalkyl-heteroaryl-.

In a nineteenth embodiment, R¹ represents optionally substituted(C₄₋₉)-spiroheterocycloalkyl-heteroaryl-.

In a twentieth embodiment, R¹ represents optionally substituted(C₃₋₇)cycloalkyl-(C₁₋₆)alkyl-heteroaryl-. In one aspect of thatembodiment, R¹ represents optionally substitutedcyclohexylmethylpyrimidinyl-.

In a twenty-first embodiment, R¹ represents optionally substituted(C₄₋₉)-bicycloalkyl-heteroaryl-.

Appositely, R¹ represents hydrogen, chloro, bromo, cyano, —OR^(a) or—CO₂R^(d); or ethyl, butynyl, phenyl, pyrrolidinyl, piperidinyl,piperazinyl, morpholinyl, 1,2,3,6-tetrahydropyridinyl, benzofuryl,thienyl, indolyl, pyrazolyl, indazolyl, isoxazolyl, thiazolyl,imidazolyl, pyridinyl, quinolinyl, pyridazinyl, pyrimidinyl, pyrazinyl,pyrrolidinylmethylphenyl, piperazinylmethylphenyl, pyridinylpiperazinyl,cyclohexylpyrazolyl, cyclohexylpyridinyl, cyclopropylpyrimidinyl,cyclobutylpyrimidinyl, cyclopentylpyrimidinyl, cyclohexylpyrimidinyl,cyclohexylpyrazinyl, cyclohexylmethylpyrimidinyl, cyclohexenylpyridinyl,cyclohexenylpyrimidinyl, bicyclo[3.1.0]hexanylpyridinyl,bicyclo[3.1.0]hexanylpyrimidinyl, bicyclo[4.1.0]heptanylpyrimidinyl,bicyclo[2.2.2]octanylpyrimidinyl, pyrrolidinylpyridinyl,tetrahydropyranylpyridinyl, piperidinylpyridinyl, piperazinylpyridinyl,morpholinylpyridinyl, thiomorpholinylpyridinyl, diazepanylpyridinyl,oxetanylpyrimidinyl, azetidinylpyrimidinyl,tetrahydrofuranylpyrimidinyl, pyrrolidinylpyrimidinyl,tetrahydropyranylpyrimidinyl, piperidinylpyrimidinyl,piperazinylpyrimidinyl,hexahydro-[1,2,5]thiadiazolo[2,3-a]-pyrazinylpyrimidinyl,morpholinylpyrimidinyl, thiomorpholinylpyrimidinyl, azepanylpyrimidinyl,oxazepanylpyrimidinyl, diazepanylpyrimidinyl, thiadiazepanylpyrimidinyl,oxetanylpyrazinyl, piperidinylpyrazinyl, morpholinylmethylthienyl,morpholinylethylpyrazolyl, 3-azabicyclo[3.1.0]hexanylpyridinyl,3-azabicyclo[3.1.0]hexanylpyridazinyl,3-azabicyclo[3.1.0]hexanylpyrimidinyl,2-oxa-5-azabicyclo[2.2.1]heptanylpyrimidinyl,3-azabicyclo[3.1.1]heptanylpyrimidinyl,3-azabicyclo[4.1.0]heptanylpyridinyl,3-azabicyclo[4.1.0]heptanylpyrimidinyl,2-oxabicyclo[2.2.2]octanylpyrimidinyl,3-azabicyclo[3.2.1]octanylpyrimidinyl,8-azabicyclo[3.2.1]octanylpyrimidinyl,3-oxa-8-azabicyclo[3.2.1]octanylpyrimidinyl,3,6-diazabicyclo[3.2.2]nonanylpyrimidinyl,3-oxa-7-azabicyclo[3.3.1]nonanylpyrimidinyl,5-azaspiro[2.3]hexanylpyrimidinyl, 5-azaspiro-[2.4]heptanylpyrimidinyl,2-azaspiro[3.3]heptanylpyrimidinyl,2-oxa-6-azaspiro[3.3]-heptanylpyrimidinyl,2-oxa-6-azaspiro[3.4]octanylpyrimidinyl,2-oxa-6-azaspiro[3.5]-nonanylpyrimidinyl,2-oxa-7-azaspiro[3.5]nonanylpyrimidinyl or2,4,8-triazaspiro[4.5]-decanylpyrimidinyl, any of which groups may beoptionally substituted by one or more substituents.

More particularly, R¹ represents hydrogen, chloro or —OR^(a); or R¹represents pyrazolyl, pyridinyl, pyrimidinyl or cyclobutylpyrimidinyl,any of which groups may be optionally substituted by one or moresubstituents.

Illustratively, R¹ represents hydrogen, chloro or —OR^(a); or R¹represents pyrazolyl or pyridinyl, either of which groups may beoptionally substituted by one or more substituents.

Typical examples of optional substituents on R¹ include one, two orthree substituents independently selected from halogen, halo(C₁₋₆)alkyl,cyano, cyano(C₁₋₆)alkyl, nitro(C₁₋₆)alkyl, C₁₋₆ alkyl, trifluoromethyl,trifluoroethyl, C₂₋₆ alkenyl, hydroxy, hydroxy(C₁₋₆)alkyl, C₁₋₆ alkoxy,trifluoroethoxy, carboxy(C₃₋₇)cycloalkyloxy, C₁₋₆ alkylthio, C₁₋₆alkylsulphonyl, (C₁₋₆)alkylsulphonyl(C₁₋₆)alkyl, oxo, amino,amino-(C₁₋₆)alkyl, C₁₋₆ alkylamino, di(C₁₋₆)alkylamino,(C₁₋₆)alkoxy(C₁₋₆)alkylamino,N—[(C₁₋₆)alkyl]-N-[hydroxy(C₁₋₆)alkyl]amino,(C₂₋₆)alkylcarbonylamino(C₁₋₆)alkyl, C₁₋₆ alkylsulphonylamino,N—[(C₁₋₆)alkyl]-N—[(C₁₋₆)alkylsulphonyl]amino,bis[(C₁₋₆)alkylsulphonyl]amino,N—[(C₁₋₆)alkyl]-N-[carboxy(C₁₋₆)alkyl]amino,carboxy(C₃₋₇)cycloalkylamino, carboxy(C₃₋₇)cycloalkyl(C₁₋₆)alkylamino,formyl, C₂₋₆ alkylcarbonyl, (C₂₋₆)alkylcarbonyloxy(C₁₋₆)alkyl, carboxy,carboxy(C₁₋₆)alkyl, C₂₋₆ alkoxycarbonyl, C₂₋₆ alkoxycarbonyl(C₁₋₆)alkyl,morpholinyl(C₁₋₆)alkoxycarbonyl, C₂₋₆ alkoxycarbonyl-methylidenyl, acarboxylic acid isostere or prodrug moiety Ω as defined herein,—(C₁₋₆)alkyl-Ω, aminocarbonyl, aminosulphonyl, (C₁₋₆)alkylsulphoximinyland [(C₁₋₆)alkyl][N—(C₁₋₆)alkyl]sulphoximinyl.

Selected examples of optional substituents on R¹ include one, two orthree substituents independently selected from C₁₋₆ alkyl, hydroxy,hydroxy(C₁₋₆)alkyl and (C₁₋₆)alkylsulphoximinyl.

Suitable examples of optional substituents on R¹ include one, two orthree substituents independently selected from C₁₋₆ alkyl.

Typical examples of particular substituents on R¹ include one, two orthree substituents independently selected from fluoro, chloro,fluoromethyl, fluoroisopropyl, cyano, cyanoethyl, nitromethyl, methyl,ethyl, isopropyl, trifluoromethyl, trifluoroethyl, ethenyl, hydroxy,hydroxymethyl, hydroxyisopropyl, methoxy, isopropoxy, trifluoroethoxy,carboxycyclobutyloxy, methylthio, methylsulphonyl, methylsulphonylethyl,oxo, amino, aminomethyl, aminoisopropyl, methylamino, dimethylamino,methoxyethylamino, N-(hydroxyethyl)-N-(methyl)amino, acetylaminomethyl,methylsulphonylamino, N-methyl-N-(methylsulphonyl)amino,bis(methylsulphonyl)amino, N-(carboxyethyl)-N-(methyl)amino,carboxycyclopentylamino, carboxycyclopropylmethylamino, formyl, acetyl,acetoxyisopropyl, carboxy, carboxymethyl, carboxyethyl, methoxycarbonyl,ethoxycarbonyl, n-butoxycarbonyl, tert-butoxycarbonyl,methoxycarbonylmethyl, ethoxycarbonylmethyl, ethoxycarbonylethyl,morpholinylethoxycarbonyl, ethoxycarbonylmethylidenyl,methylsulphonylaminocarbonyl, acetylaminosulphonyl,methoxyaminocarbonyl, tetrazolyl, tetrazolylmethyl, hydroxyoxadiazolyl,aminocarbonyl, aminosulphonyl, methylsulphoximinyl and(methyl)(N-methyl)sulphoximinyl.

Selected examples of particular substituents on R¹ include one, two orthree substituents independently selected from methyl, hydroxy,hydroxyisopropyl and methylsulphoximinyl.

Suitable examples of particular substituents on R¹ include one, two orthree substituents independently selected from methyl.

In a particular embodiment, R¹ is substituted by hydroxy(C₁₋₆)alkyl. Inone aspect of that embodiment, R¹ is substituted by hydroxyisopropyl,especially 2-hydroxyprop-2-yl.

Selected values of R¹ include hydrogen, chloro, bromo, cyano, —OR^(a),—CO₂R^(d), methoxycarbonylethyl, ethoxycarbonylethyl, hydroxybutynyl,chlorophenyl, hydroxyphenyl, methylsulphonylphenyl, aminomethylphenyl,aminoisopropylphenyl, acetylaminomethylphenyl, acetylphenyl,methoxycarbonylphenyl, aminocarbonylphenyl, aminosulphonylphenyl,acetylaminosulphonylphenyl, (methoxycarbonyl)(methyl)-pyrrolidinyl,oxopiperidinyl, ethoxycarbonylpiperidinyl, methylsulphonylpiperazinyl,morpholinyl, methylsulphonyl-1,2,3,6-tetrahydropyridinyl,acetyl-1,2,3,6-tetrahydropyridinyl,tert-butoxycarbonyl-1,2,3,6-tetrahydropyridinyl,methoxycarbonylmethyl-1,2,3,6-tetrahydropyridinyl, benzofuryl, thienyl,indolyl, pyrazolyl, methylpyrazolyl, dimethylpyrazolyl,(methyl)[N-methyl-N-(methylsulfonyl)amino]pyrazolyl, methylindazolyl,dimethylisoxazolyl, hydroxyisopropylthiazolyl, methylimidazolyl,dimethylimidazolyl, pyridinyl, fluoropyridinyl, cyanopyridinyl,methylpyridinyl, (cyano)(methyl)pyridinyl, dimethylpyridinyl,trifluoromethylpyridinyl, ethenylpyridinyl, hydroxyisopropylpyridinyl,methoxypyridinyl, (methoxy)(methyl)pyridinyl, isopropoxypyridinyl,trifluoroethoxypyridinyl, (methyl)(trifluoroethoxy)pyridinyl,methylsulphonylpyridinyl, oxopyridinyl, (methyl)(oxo)pyridinyl,(dimethyl)(oxo)pyridinyl, aminopyridinyl, methylaminopyridinyl,dimethylaminopyridinyl, methoxyethylaminopyridinyl,N-(hydroxyethyl)-N-(methyl)aminopyridinyl,methylsulphonylaminopyridinyl, [bis(methylsulphonyl)amino]pyridinyl,carboxypyridinyl, quinolinyl, hydroxypyridazinyl, pyrimidinyl,fluoroisopropylpyrimidinyl, hydroxyisopropylpyrimidinyl,methoxypyrimidinyl, carboxycyclobutyloxypyrimidinyl,methylthiopyrimidinyl, methylsulphonylpyrimidinyl, oxopyrimidinyl,aminopyrimidinyl, dimethylaminopyrimidinyl,methoxyethylaminopyrimidinyl,N-(carboxyethyl)-N-(methyl)aminopyrimidinyl,carboxycyclopentylaminopyrimidinyl,carboxycyclopropylmethylaminopyrimidinyl, acetoxyisopropylpyrimidinyl,ethoxycarbonylethylpyrimidinyl, hydroxypyrazinyl,hydroxyisopropylpyrazinyl, pyrrolidinylmethylphenyl,piperazinylmethylphenyl, pyridinylpiperazinyl,carboxycyclohexylpyrazolyl, carboxycyclohexylpyridinyl,fluoromethylcyclopropylpyrimidinyl,acetylaminomethylcyclopropylpyrimidinyl, hydroxycyclobutylpyrimidinyl,carboxycyclopentylpyrimidinyl, carboxycyclohexylpyrimidinyl,(carboxy)(methyl)cyclohexylpyrimidinyl,(carboxy)(hydroxy)cyclohexylpyrimidinyl,carboxymethylcyclohexylpyrimidinyl, ethoxycarbonylcyclohexylpyrimidinyl,(methoxycarbonyl)(methyl)cyclohexylpyrimidinyl,(ethoxycarbonyl)-(methyl)cyclohexylpyrimidinyl,carboxycyclohexylpyrazinyl, carboxycyclohexylmethylpyrimidinyl,carboxycyclohexenylpyridinyl, carboxycyclohexenylpyrimidinyl,ethoxycarbonylcyclohexenylpyrimidinyl,carboxybicyclo[3.1.0]hexanylpyridinyl,carboxybicyclo[3.1.0]hexanylpyrimidinyl,ethoxycarbonylbicyclo[3.1.0]hexanylpyrimidinyl,carboxybicyclo[4.1.0]heptanylpyrimidinyl,carboxybicyclo[2.2.2]octanylpyrimidinyl, pyrrolidinylpyridinyl,hydroxypyrrolidinylpyridinyl, hydroxytetrahydropyranylpyridinyl,piperidinylpyridinyl, acetylpiperidinylpyridinyl,(carboxy)(methyl)piperidinylpyridinyl,[(carboxy)(methyl)piperidinyl](fluoro)pyridinyl,[(carboxy)(methyl)piperidinyl](chloro)pyridinyl, piperazinylpyridinyl,(methyl)-(piperazinyl)pyridinyl, cyanoethylpiperazinylpyridinyl,trifluoroethylpiperazinylpyridinyl, methylsulphonylpiperazinylpyridinyl,methylsulphonylethylpiperazinylpyridinyl, oxopiperazinylpyridinyl,acetylpiperazinylpyridinyl,(tert-butoxycarbonylpiperazinyl)-(methyl)pyridinyl,carboxymethylpiperazinylpyridinyl, carboxyethylpiperazinylpyridinyl,ethoxycarbonylmethylpiperazinylpyridinyl,ethoxycarbonylethylpiperazinylpyridinyl, morpholinylpyridinyl,thiomorpholinylpyridinyl, oxothiomorpholinylpyridinyl,dioxothiomorpholinylpyridinyl, oxodiazepanylpyridinyl,fluorooxetanylpyrimidinyl, hydroxyoxetanylpyrimidinyl,hydroxyazetidinylpyrimidinyl, (hydroxy)(methyl)-azetidinylpyrimidinyl,carboxyazetidinylpyrimidinyl,(tert-butoxycarbonyl)(hydroxy)-azetidinylpyrimidinyl,tetrazolylazetidinylpyrimidinyl, hydroxytetrahydrofuranylpyrimidinyl,hydroxypyrrolidinylpyrimidinyl, carboxypyrrolidinylpyrimidinyl,(carboxy)(methyl)pyrrolidinylpyrimidinyl,carboxymethylpyrrolidinylpyrimidinyl,ethoxycarbonylpyrrolidinylpyrimidinyl,fluorotetrahydropyranylpyrimidinyl, hydroxytetrahydropyranylpyrimidinyl,difluoropiperidinylpyrimidinyl, (cyano)(methyl)-piperidinylpyrimidinyl,(hydroxy)(nitromethyl)piperidinylpyrimidinyl,(hydroxy)-(methyl)piperidinylpyrimidinyl,(hydroxy)(trifluoromethyl)piperidinylpyrimidinyl,(hydroxymethyl)(methyl)piperidinylpyrimidinyl,methylsulphonylpiperidinylpyrimidinyl, oxopiperidinylpyrimidinyl,(formyl)(methyl)piperidinylpyrimidinyl, carboxypiperidinylpyrimidinyl,(carboxy)(fluoro)piperidinylpyrimidinyl,(carboxy)(methyl)piperidinylpyrimidinyl,(carboxy)(ethyl)piperidinylpyrimidinyl,(carboxy)(trifluoromethyl)-piperidinylpyrimidinyl,(carboxy)(hydroxy)piperidinylpyrimidinyl,(carboxy)-(hydroxymethyl)piperidinylpyrimidinyl,(carboxy)(methoxy)piperidinylpyrimidinyl,(amino)(carboxy)piperidinylpyrimidinyl,carboxymethylpiperidinylpyrimidinyl,methoxycarbonylpiperidinylpyrimidinyl,ethoxycarbonylpiperidinylpyrimidinyl,(ethoxycarbonyl)(fluoro)piperidinylpyrimidinyl,(methoxycarbonyl)(methyl)piperidinylpyrimidinyl,(ethyl)(methoxycarbonyl)piperidinylpyrimidinyl,(isopropyl)-(methoxycarbonyl)piperidinylpyrimidinyl,(ethoxycarbonyl)(methyl)piperidinylpyrimidinyl,(n-butoxycarbonyl)(methyl)piperidinylpyrimidinyl,(ethoxycarbonyl)-(trifluoromethyl)piperidinylpyrimidinyl,(ethoxycarbonyl)(hydroxymethyl)piperidinylpyrimidinyl,(methoxy)(methoxycarbonyl)piperidinylpyrimidinyl,(carboxy)-(methoxycarbonyl)piperidinylpyrimidinyl,(methyl)(morpholinylethoxycarbonyl)-piperidinylpyrimidinyl,ethoxycarbonylmethylpiperidinylpyrimidinyl,methylsulphonylaminocarbonylpiperidinylpyrimidinyl,acetylaminosulphonylpiperidinylpyrimidinyl,methoxyaminocarbonylpiperidinylpyrimidinyl,tetrazolylpiperidinylpyrimidinyl,hydroxyoxadiazolylpiperidinylpyrimidinyl,aminosulphonylpiperidinylpyrimidinyl, piperazinylpyrimidinyl,methylsulphonylpiperazinylpyrimidinyl, oxopiperazinylpyrimidinyl,carboxypiperazinylpyrimidinyl, carboxyethylpiperazinylpyrimidinyl,tert-butoxycarbonylpiperazinylpyrimidinyl,tetrazolylmethylpiperazinylpyrimidinyl,trioxohexahydro-[1,2,5]thiadiazolo[2,3-a]pyrazinylpyrimidinyl,morpholinylpyrimidinyl, dimethylmorpholinylpyrimidinyl,hydroxymethylmorpholinylpyrimidinyl, carboxymorpholinylpyrimidinyl,(carboxy)(methyl)morpholinylpyrimidinyl,carboxymethylmorpholinylpyrimidinyl, thiomorpholinylpyrimidinyl,dioxothiomorpholinylpyrimidinyl, carboxyazepanylpyrimidinyl,carboxyoxazepanylpyrimidinyl, oxodiazepanylpyrimidinyl,(oxodiazepanyl)(trifluoromethyl)pyrimidinyl,(oxodiazepanyl)(methoxy)pyrimidinyl, (methyl)(oxo)diazepanylpyrimidinyl,dioxothiadiazepanylpyrimidinyl, hydroxyoxetanylpyrazinyl,(carboxy)(methyl)piperidinylpyrazinyl,(ethoxycarbonyl)(methyl)piperidinylpyrazinyl, morpholinylmethylthienyl,morpholinylethylpyrazolyl, carboxy-3-azabicyclo-[3.1.0]hexanylpyridinyl,carboxy-3-azabicyclo[3.1.0]hexanylpyridazinyl,carboxy-3-azabicyclo[3.1.0]hexanylpyrimidinyl,(carboxy)(methyl)-3-azabicyclo[3.1.0]hexanylpyrimidinyl,methoxycarbonyl-3-azabicyclo[3.1.0]hexanylpyrimidinyl,ethoxycarbonyl-3-azabicyclo[3.1.0]hexanylpyrimidinyl,2-oxa-5-azabicyclo[2.2.1]heptanylpyrimidinyl,carboxy-2-oxa-5-azabicyclo[2.2.1]heptanylpyrimidinyl,carboxy-3-azabicyclo[3.1.1]-heptanylpyrimidinyl,carboxy-3-azabicyclo[4.1.0]heptanylpyridinyl,carboxy-3-azabicyclo[4.1.0]heptanylpyrimidinyl,methoxycarbonyl-3-azabicyclo[4.1.0]heptanylpyrimidinyl,ethoxycarbonyl-3-azabicyclo[4.1.0]heptanylpyrimidinyl,(hydroxy)(methyl)-(oxo)-2-oxabicyclo[2.2.2]octanylpyrimidinyl,carboxy-3-azabicyclo[3.2.1]octanylpyrimidinyl,methoxycarbonyl-3-azabicyclo[3.2.1]octanylpyrimidinyl,oxo-8-azabicyclo-[3.2.1]octanylpyrimidinyl,ethoxycarbonylmethylidenyl-8-azabicyclo[3.2.1]octanylpyrimidinyl,3-oxa-8-azabicyclo[3.2.1]octanylpyrimidinyl,oxo-3,6-diazabicyclo[3.2.2]-nonanylpyrimidinyl,carboxy-3-oxa-7-azabicyclo[3.3.1]nonanylpyrimidinyl,carboxy-5-azaspiro[2.3]hexanylpyrimidinyl,(carboxy)(methyl)-5-azaspiro[2.3]hexanylpyrimidinyl,carboxy-5-azaspiro[2.4]heptanylpyrimidinyl,carboxy-2-azaspiro[3.3]heptanylpyrimidinyl,2-oxa-6-azaspiro[3.3]heptanylpyrimidinyl,2-oxa-6-azaspiro[3.4]octanylpyrimidinyl,2-oxa-6-azaspiro[3.5]nonanylpyrimidinyl,2-oxa-7-azaspiro[3.5]nonanylpyrimidinyl and(dioxo)(methyl)-2,4,8-triazaspiro[4.5]decanylpyrimidinyl. Additionalvalues include methylsulphoximinylpyridinyl and(dihydroxy)(methyl)cyclobutylpyrimidinyl.

Typical values of R¹ include hydrogen, chloro, —OR^(a), methylpyrazolyl,pyridinyl, methylsulphoximinylpyridinyl, hydroxyisopropylpyrimidinyl and(dihydroxy)(methyl)-cyclobutylpyrimidinyl.

Illustrative values of R¹ include hydrogen, chloro, —OR^(a),methylpyrazolyl and pyridinyl.

Typically, R² represents hydrogen, halogen, trifluoromethyl or —OR^(a);or R² represents optionally substituted C₁₋₆ alkyl.

Typical examples of optional substituents on R² include C₂₋₆alkoxycarbonyl.

Typical examples of particular substituents on R² includeethoxycarbonyl.

In a first embodiment, R² represents hydrogen. In a second embodiment,R² represents halogen. In one aspect of that embodiment, R² representsfluoro. In another aspect of that embodiment, R² represents chloro. In athird embodiment, R² represents trifluoromethyl. In a fourth embodiment,R² represents —OR^(a). In a fifth embodiment, R² represents optionallysubstituted C₁₋₆ alkyl. In one aspect of that embodiment, R² representsunsubstituted methyl. In another aspect of that embodiment, R²represents unsubstituted ethyl. In a further aspect of that embodiment,R² represents monosubstituted methyl or monosubstituted ethyl.

Typical values of R² include hydrogen, fluoro, chloro, trifluoromethyl,—OR^(a), methyl and ethoxycarbonylethyl.

Typically, R³ represents hydrogen, halogen or C₁₋₆ alkyl.

In a first embodiment, R³ represents hydrogen. In a second embodiment,R³ represents halogen. In one aspect of that embodiment, R³ representsfluoro. In a third embodiment, R³ represents C₁₋₆ alkyl. In one aspectof that embodiment, R³ represents methyl. In another aspect of thatembodiment, R³ represents ethyl.

Suitably, R⁴ represents hydrogen or methyl.

In a first embodiment, R⁴ represents hydrogen. In a second embodiment,R⁴ represents C₁₋₆ alkyl, especially methyl.

Suitably, R⁵ represents hydrogen, methyl or ethyl.

In a first embodiment, R⁵ represents hydrogen. In a second embodiment,R⁵ represents C₁₋₆ alkyl, especially methyl or ethyl. In one aspect ofthat embodiment, R⁵ represents methyl. In another aspect of thatembodiment, R⁵ represents ethyl.

Typical examples of suitable substituents on R^(a), R^(b), R^(c), R^(d)or R^(e), or on the heterocyclic moiety —NR^(b)R^(c), include halogen,C₁₋₆ alkyl, C₁₋₆ alkoxy, difluoromethoxy, trifluoromethoxy, C₁₋₆alkoxy(C₁₋₆)alkyl, C₁₋₆ alkylthio, C₁₋₆ alkylsulphinyl, C₁₋₆alkylsulphonyl, hydroxy, hydroxy(C₁₋₆)alkyl, amino(C₁₋₆)alkyl, cyano,trifluoromethyl, oxo, C₂₋₆ alkylcarbonyl, carboxy, C₂₋₆ alkoxycarbonyl,C₂₋₆ alkylcarbonyloxy, amino, C₁₋₆ alkylamino, di(C₁₋₆)alkylamino,phenylamino, pyridinylamino, C₂₋₆ alkylcarbonylamino, C₂₋₆alkylcarbonylamino(C₁₋₆)alkyl, C₂₋₆ alkoxycarbonylamino, C₁₋₆alkylsulphonylamino, aminocarbonyl, C₁₋₆ alkylaminocarbonyl anddi(C₁₋₆)alkylaminocarbonyl.

Typical examples of specific substituents on R^(a), R^(b), R^(c), R^(d)or R^(e), or on the heterocyclic moiety —NR^(b)R^(c), include fluoro,chloro, bromo, methyl, ethyl, isopropyl, methoxy, isopropoxy,difluoromethoxy, trifluoromethoxy, methoxymethyl, methylthio, ethylthio,methylsulphinyl, methylsulphonyl, hydroxy, hydroxymethyl, hydroxyethyl,aminomethyl, cyano, trifluoromethyl, oxo, acetyl, carboxy,methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, acetoxy, amino,methylamino, ethylamino, dimethylamino, phenylamino, pyridinylamino,acetylamino, tert-butoxycarbonylamino, acetylaminomethyl,methylsulphonylamino, aminocarbonyl, methylaminocarbonyl anddimethylaminocarbonyl.

Suitably, Ra represents C₁₋₆ alkyl, aryl(C₁₋₆)alkyl orheteroaryl(C₁₋₆)alkyl, any of which groups may be optionally substitutedby one or more substituents.

Selected values of R^(a) include methyl, ethyl, benzyl andisoindolylpropyl, any of which groups may be optionally substituted byone or more substituents.

Selected examples of suitable substituents on R^(a) include C₁₋₆ alkoxyand oxo.

Selected examples of specific substituents on R^(a) include methoxy andoxo.

In one embodiment, R^(a) represents optionally substituted C₁₋₆ alkyl.In one aspect of that embodiment, R^(a) ideally represents unsubstitutedC₁₋₆ alkyl, especially methyl. In another aspect of that embodiment,R^(a) ideally represents substituted C₁₋₆ alkyl, e.g. methoxyethyl. Inanother embodiment, R^(a) represents optionally substituted aryl. In oneaspect of that embodiment, R^(a) represents unsubstituted aryl,especially phenyl. In another aspect of that embodiment, R^(a)represents monosubstituted aryl, especially methylphenyl. In anotherembodiment, R^(a) represents optionally substituted aryl(C₁₋₆)alkyl,ideally unsubstituted aryl(C₁₋₆)alkyl, especially benzyl. In a furtherembodiment, R^(a) represents optionally substituted heteroaryl. In afurther embodiment, R^(a) represents optionally substitutedheteroaryl(C₁₋₆)alkyl, e.g. dioxoisoindolylpropyl.

Specific values of R^(a) include methyl, methoxyethyl, benzyl anddioxoisoindolylpropyl.

In a particular aspect, R^(b) represents hydrogen or trifluoromethyl; orC₁₋₆ alkyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkyl(C₁₋₆)alkyl, aryl,aryl(C₁₋₆)alkyl, C₃₋₇ heterocycloalkyl, C₃₋₇heterocycloalkyl(C₁₋₆)alkyl, heteroaryl or heteroaryl(C₁₋₆)alkyl, any ofwhich groups may be optionally substituted by one or more substituents.

Selected values of R^(b) include hydrogen; or C₁₋₆ alkyl,aryl(C₁₋₆)alkyl, C₃₋₇ heterocycloalkyl or C₃₋₇heterocycloalkyl(C₁₋₆)alkyl, any of which groups may be optionallysubstituted by one or more substituents.

Typical values of R^(b) include hydrogen and C₁₋₆ alkyl.

Illustratively, R^(b) represents hydrogen or trifluoromethyl; or methyl,ethyl, n-propyl, isopropyl, n-butyl, 2-methylpropyl, tert-butyl, pentyl,hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl,cyclohexylmethyl, phenyl, benzyl, phenylethyl, azetidinyl,tetrahydrofuryl, tetrahydrothienyl, pyrrolidinyl, piperidinyl,homopiperidinyl, morpholinyl, azetidinylmethyl, tetrahydrofurylmethyl,pyrrolidinylmethyl, pyrrolidinylethyl, pyrrolidinylpropyl,thiazolidinylmethyl, imidazolidinylethyl, piperidinylmethyl,piperidinylethyl, tetrahydroquinolinylmethyl, piperazinylpropyl,morpholinylmethyl, morpholinylethyl, morpholinylpropyl, pyridinyl,indolylmethyl, pyrazolylmethyl, pyrazolylethyl, imidazolylmethyl,imidazolylethyl, benzimidazolylmethyl, triazolylmethyl, pyridinylmethylor pyridinylethyl, any of which groups may be optionally substituted byone or more substituents.

Representative values of R^(b) include hydrogen; or methyl, ethyl,n-propyl, benzyl, pyrrolidinyl or morpholinylpropyl, any of which groupsmay be optionally substituted by one or more substituents.

Selected examples of suitable substituents on R^(b) include C₁₋₆ alkoxy,C₁₋₆ alkylthio, C₁₋₆ alkylsulphinyl, C₁₋₆ alkylsulphonyl, hydroxy,cyano, C₂₋₆ alkoxycarbonyl, di-(C₁₋₆)alkylamino and C₂₋₆alkoxycarbonylamino.

Selected examples of specific substituents on R^(b) include methoxy,methylthio, methylsulphinyl, methylsulphonyl, hydroxy, cyano,tert-butoxycarbonyl, dimethylamino and tert-butoxycarbonylamino.

Specific values of R^(b) include hydrogen, methyl, methoxyethyl,methylthioethyl, methylsulphinylethyl, methylsulphonylethyl,hydroxyethyl, cyanoethyl, dimethylaminoethyl,tert-butoxycarbonylaminoethyl, dihydroxypropyl, benzyl, pyrrolidinyl,tert-butoxycarbonylpyrrolidinyl and morpholinylpropyl.

In one embodiment, R^(b) represents hydrogen. In another embodiment,R^(b) represents C₁₋₆ alkyl, especially methyl.

Selected values of Rc include hydrogen; or C₁₋₆ alkyl, C₃₋₇ cycloalkylor C₃₋₇ heterocycloalkyl, any of which groups may be optionallysubstituted by one or more substituents.

In a particular aspect, Rc represents hydrogen, C₁₋₆ alkyl or C₃₋₇cycloalkyl.

Representative values of R^(c) include hydrogen; or methyl, cyclobutyl,cyclopentyl, cyclohexyl, tetrahydropyranyl and piperidinyl, any of whichgroups may be optionally substituted by one or more substituents.

Selected examples of suitable substituents on Rc include C₂₋₆alkylcarbonyl and C₂₋₆ alkoxycarbonyl.

Selected examples of specific substituents on R^(c) include acetyl andtert-butoxycarbonyl.

Specific values of R^(c) include hydrogen, methyl, cyclobutyl,cyclopentyl, cyclohexyl, tetrahydropyranyl, acetylpiperidinyl andtert-butoxycarbonylpiperidinyl,

Suitably, R^(c) represents hydrogen or C₁₋₆ alkyl. In one embodiment, Rcis hydrogen. In another embodiment, Rc represents C₁₋₆ alkyl, especiallymethyl or ethyl, particularly methyl. In a further embodiment, Rcrepresents C₃₋₇ cycloalkyl, e.g. cyclopropyl, cyclobutyl, cyclopentyl orcyclohexyl.

Alternatively, the moiety —NR^(b)R^(c) may suitably representazetidin-1-yl, pyrrolidin-1-yl, oxazolidin-3-yl, isoxazolidin-2-yl,thiazolidin-3-yl, isothiazolidin-2-yl, piperidin-1-yl, morpholin-4-yl,thiomorpholin-4-yl, piperazin-1-yl, homopiperidin-1-yl,homomorpholin-4-yl or homopiperazin-1-yl, any of which groups may beoptionally substituted by one or more substituents.

Selected examples of suitable substituents on the heterocyclic moiety—NR^(b)R^(c) include C₁₋₆ alkyl, C₁₋₆ alkylsulphonyl, hydroxy,hydroxy(C₁₋₆)alkyl, amino(C₁₋₆)alkyl, cyano, oxo, C₂₋₆ alkylcarbonyl,carboxy, C₂₋₆ alkoxycarbonyl, amino, C₂₋₆ alkylcarbonylamino, C₂₋₆alkylcarbonylamino(C₁₋₆)alkyl, C₂₋₆ alkoxycarbonylamino, C₁₋₆alkylsulphonylamino and aminocarbonyl.

Selected examples of specific substituents on the heterocyclic moiety—NR^(b)R^(c) include methyl, methylsulphonyl, hydroxy, hydroxymethyl,aminomethyl, cyano, oxo, acetyl, carboxy, ethoxycarbonyl, amino,acetylamino, acetylaminomethyl, tert-butoxycarbonylamino,methylsulphonylamino and aminocarbonyl.

Specific values of the moiety —NR^(b)R^(c) include azetidin-1-yl,hydroxyazetidin-1-yl, hydroxymethylazetidin-1-yl,(hydroxy)(hydroxymethyl)azetidin-1-yl, aminomethyl-azetidin-1-yl,cyanoazetidin-1-yl, carboxyazetidin-1-yl, aminoazetidin-1-yl,aminocarbonylazetidin-1-yl, pyrrolidin-1-yl, aminomethylpyrrolidin-1-yl,oxopyrrolidin-1-yl, acetylaminomethylpyrrolidin-1-yl,tert-butoxycarbonylaminopyrrolidin-1-yl, oxooxazolidin-3-yl,hydroxyisoxazolidin-2-yl, thiazolidin-3-yl, oxothiazolidin-3-yl,dioxo-isothiazolidin-2-yl, piperidin-1-yl, hydroxypiperidin-1-yl,hydroxymethylpiperidin-1-yl, aminopiperidin-1-yl,acetylaminopiperidin-1-yl, tert-butoxycarbonylaminopiperidin-1-yl,methylsulphonylaminopiperidin-1-yl, morpholin-4-yl, piperazin-1-yl,methylpiperazin-1-yl, methylsulphonylpiperazin-1-yl, oxopiperazin-1-yl,acetylpiperazin-1-yl, ethoxycarbonylpiperazin-1-yl andoxohomopiperazin-1-yl.

Suitably, R^(d) represents hydrogen; or C₁₋₆ alkyl, aryl or heteroaryl,any of which groups may be optionally substituted by one or moresubstituents.

Selected examples of suitable values for R^(d) include hydrogen, methyl,ethyl, isopropyl, 2-methylpropyl, tert-butyl, cyclopropyl, cyclobutyl,phenyl, thiazolidinyl, thienyl, imidazolyl and thiazolyl, any of whichgroups may be optionally substituted by one or more substituents.

Selected examples of suitable substituents on R^(d) include halogen,C₁₋₆ alkyl, C₁₋₆ alkoxy, oxo, C₂₋₆ alkylcarbonyloxy anddi(C₁₋₆)alkylamino.

Selected examples of particular substituents on R^(d) include fluoro,methyl, methoxy, oxo, acetoxy and dimethylamino.

In one embodiment, R^(d) represents hydrogen. In another embodiment,R^(d) represents optionally substituted C₁₋₆ alkyl. In one aspect ofthat embodiment, R^(d) ideally represents unsubstituted C₁₋₆ alkyl, e.g.methyl, ethyl, isopropyl, 2-methylpropyl or tert-butyl, especiallymethyl. In another aspect of that embodiment, R^(d) ideally representssubstituted C₁₋₆ alkyl, e.g. substituted methyl or substituted ethyl,including acetoxymethyl, dimethylaminomethyl and trifluoroethyl. Inanother embodiment, R^(d) represents optionally substituted aryl. In oneaspect of that embodiment, R^(d) represents unsubstituted aryl,especially phenyl. In another aspect of that embodiment, R^(d)represents monosubstituted aryl, especially methylphenyl. In a furtheraspect of that embodiment, R^(d) represents disubstituted aryl, e.g.dimethoxyphenyl. In a further embodiment, R^(d) represents optionallysubstituted heteroaryl, e.g. thienyl, chlorothienyl, methylthienyl,methylimidazolyl or thiazolyl. In another embodiment, R^(d) representsoptionally substituted C₃₋₇ cycloalkyl, e.g. cyclopropyl or cyclobutyl.In a further embodiment, R^(d) represents optionally substituted C₃₋₇heterocycloalkyl, e.g. thiazolidinyl or oxothiazolidinyl.

Selected examples of specific values for R^(d) include hydrogen, methyl,acetoxymethyl, dimethylaminomethyl, ethyl, trifluoroethyl, isopropyl,2-methylpropyl, tert-butyl, cyclopropyl, cyclobutyl, phenyl,dimethoxyphenyl, thiazolidinyl, oxothiazolidinyl, thienyl,chlorothienyl, methylthienyl, methylimidazolyl and thiazolyl.

Suitably, R^(e) represents C₁₋₆ alkyl or aryl, either of which groupsmay be optionally substituted by one or more substituents.

Selected examples of suitable substituents on R^(e) include C₁₋₆ alkyl,especially methyl.

In one embodiment, R^(e) represents optionally substituted C₁₋₆ alkyl,ideally unsubstituted C₁₋₆ alkyl, e.g. methyl or propyl, especiallymethyl. In another embodiment, R^(e) represents optionally substitutedaryl. In one aspect of that embodiment, R^(e) represents unsubstitutedaryl, especially phenyl. In another aspect of that embodiment, R^(e)represents monosubstituted aryl, especially methylphenyl. In a furtherembodiment, R^(e) represents optionally substituted heteroaryl.

Selected values of R^(e) include methyl, propyl and methylphenyl.

One sub-class of compounds according to the invention is represented bythe compounds of formula (IIA) and N-oxides thereof, andpharmaceutically acceptable salts and solvates thereof, and glucuronidederivatives thereof, and co-crystals thereof:

wherein

R¹¹ represents hydrogen, halogen or —OR^(a); or R¹¹ represents C₁₋₆alkyl, C₂₋₆ alkynyl, aryl, C₃₋₇ heterocycloalkyl, C₃₋₇heterocycloalkenyl, heteroaryl, (C₃₋₇)heterocycloalkyl(C₁₋₆)alkyl-aryl-,heteroaryl(C₃₋₇)heterocycloalkyl-, (C₃₋₇)cycloalkyl-heteroaryl-,(C₃₋₇)cyclo alkyl(C₁₋₆)alkyl-hetero aryl-,(C₄₋₇)cycloalkenyl-heteroaryl-, (C₄₋₉)bicycloalkyl-heteroaryl-,(C₃₋₇)heterocycloalkyl-heteroaryl-, (C₃₋₇)hetero cycloalkyl(C₁₋₆)alkyl-hetero aryl-, (C₃₋₇)hetero cyclo alkenyl-hetero aryl-,(C₄₋₉)heterobicycloalkyl-heteroaryl- or(C₄₋₉)spiroheterocycloalkyl-heteroaryl-, any of which groups may beoptionally substituted by one or more substituents;

R¹² represents represents hydrogen, halogen, trifluoromethyl oroptionally substituted C₁₋₆ alkyl;

R¹⁵ and R¹⁶ independently represent hydrogen, halogen, cyano, nitro,C₁₋₆ alkyl, trifluoromethyl, hydroxy, C₁₋₆ alkoxy, difluoromethoxy,trifluoromethoxy, C₁₋₆ alkylthio, C₁₋₆ alkylsulfinyl, C₁₋₆alkylsulfonyl, amino, C₁₋₆ alkylamino, di(C₁₋₆)alkylamino, arylamino,C₂₋₆ alkylcarbonylamino, C₁₋₆ alkylsulfonylamino, formyl, C₂₋₆alkylcarbonyl, C₃₋₆ cycloalkylcarbonyl, C₃₋₆ heterocycloalkylcarbonyl,carboxy, C₂₋₆ alkoxycarbonyl, aminocarbonyl, C₁₋₆ alkylaminocarbonyl,di(C₁₋₆)alkylaminocarbonyl, aminosulfonyl, C₁₋₆ alkylaminosulfonyl ordi(C₁₋₆)alkylaminosulfonyl; and

E, Q, Z and Ra are as defined above.

Examples of optional substituents which may be present on R¹¹ includeone, two or three substituents independently selected from halogen,halo(C₁₋₆)alkyl, cyano, cyano(C₁₋₆)alkyl, nitro, nitro(C₁₋₆)alkyl, C₁₋₆alkyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl,C₂₋₆ alkenyl, hydroxy, hydroxy(C₁₋₆)alkyl, C₁₋₆ alkoxy, difluoromethoxy,trifluoromethoxy, trifluoroethoxy, carboxy(C₃₋₇)cycloalkyloxy, C₁₋₃alkylenedioxy, C₁₋₆ alkoxy(C₁₋₆)alkyl, C₁₋₆ alkylthio, C₁₋₆alkylsulphinyl, C₁₋₆ alkylsulphonyl, (C₁₋₆)alkylsulphonyl(C₁₋₆)alkyl,oxo, amino, amino(C₁₋₆)alkyl, C₁₋₆ alkylamino, di(C₁₋₆)alkylamino,hydroxy(C₁₋₆)alkylamino, C₁₋₆ alkoxyamino, (C₁₋₆)alkoxy(C₁₋₆)alkylamino,[(C₁₋₆)alkoxy](hydroxy)(C₁₋₆)alkylamino,[(C₁₋₆)alkylthio](hydroxy)(C₁₋₆)alkylamino,N—[(C₁₋₆)alkyl]-N-[hydroxy(C₁₋₆)alkyl]amino,di(C₁₋₆)alkylamino(C₁₋₆)alkylamino,N-[di(C₁₋₆)alkylamino(C₁₋₆)alkyl]-N-[hydroxy(C₁₋₆)alkyl]amino,hydroxy(C₁₋₆)alkyl-(C₃₋₇)cycloalkylamino,(hydroxy)[(C₃₋₇)cycloalkyl(C₁₋₆)alkyl]amino,(C₃₋₇)heterocycloalkyl(C₁₋₆)alkylamino,oxo(C₃₋₇)heterocycloalkyl(C₁₋₆)alkylamino, (C₁₋₆)alkylheteroarylamino,heteroaryl(C₁₋₆)alkylamino, (C₁₋₆)alkylheteroaryl(C₁₋₆)alkylamino, C₂₋₆alkylcarbonylamino, N—[(C₁₋₆)alkyl]-N—[(C₂₋₆)alkylcarbonyl]amino,(C₂₋₆)alkylcarbonylamino(C₁₋₆)alkyl, C₃₋₆ alkenylcarbonylamino,bis[(C₃₋₆)alkenylcarbonyl]amino,N—[(C₁₋₆)alkyl]-N—[(C₃₋₇)cycloalkylcarbonyl]amino, C₂₋₆alkoxycarbonylamino, C₂₋₆ alkoxycarbonyl(C₁₋₆)alkylamino, C₁₋₆alkylaminocarbonylamino, C₁₋₆ alkylsulphonylamino,N—[(C₁₋₆)alkyl]-N—[(C₁₋₆)alkylsulphonyl]amino,bis[(C₁₋₆)alkylsulphonyl]amino,N—[(C₁₋₆)alkyl]-N-[carboxy(C₁₋₆)alkyl]amino,carboxy(C₃₋₇)cycloalkylamino, carboxy-(C₃₋₇)cycloalkyl(C₁₋₆)alkylamino,formyl, C₂₋₆ alkylcarbonyl, (C₃₋₇)cycloalkylcarbonyl, phenylcarbonyl,(C₂₋₆)alkylcarbonyloxy(C₁₋₆)alkyl, carboxy, carboxy(C₁₋₆)alkyl, C₂₋₆alkoxycarbonyl, C₂₋₆ alkoxycarbonyl(C₁₋₆)alkyl,morpholinyl(C₁₋₆)alkoxycarbonyl, C₂₋₆ alkoxycarbonylmethylidenyl, acarboxylic acid isostere or prodrug moiety Ω as defined herein,—(C₁₋₆)alkyl-Ω, aminocarbonyl, C₁₋₆ alkylaminocarbonyl,hydroxy(C₁₋₆)alkylaminocarbonyl, di(C₁₋₆)alkylaminocarbonyl,aminocarbonyl(C₁₋₆)alkyl, aminosulphonyl, di(C₁₋₆)alkylamino-sulphonyl,(C₁₋₆)alkylsulphoximinyl and [(C₁₋₆)alkyl][N—(C₁₋₆)alkyl]-sulphoximinyl.

Examples of particular substituents on R¹¹ include fluoro, chloro,bromo, fluoromethyl, fluoroisopropyl, cyano, cyanoethyl, nitro,nitromethyl, methyl, ethyl, isopropyl, isobutyl, tert-butyl,difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, ethenyl,hydroxy, hydroxymethyl, hydroxyisopropyl, methoxy, isopropoxy,difluoromethoxy, trifluoromethoxy, trifluoroethoxy,carboxycyclobutyloxy, methylenedioxy, ethylenedioxy, methoxymethyl,methoxyethyl, methylthio, methylsulphinyl, methylsulphonyl,methylsulphonylethyl, oxo, amino, aminomethyl, aminoisopropyl,methylamino, ethylamino, dimethylamino, hydroxyethylamino,hydroxypropylamino, (hydroxy)(methyl)propylamino, methoxyamino,methoxyethylamino, (hydroxy)-(methoxy)(methyl)propylamino,(hydroxy)(methylthio)butylamino, N-(hydroxyethyl)-N-(methyl)amino,dimethylaminoethylamino, (dimethylamino)(methyl)propylamino,N-(dimethylaminoethyl)-N-(hydroxyethyl)amino,hydroxymethylcyclopentylamino, hydroxycyclobutylmethylamino,(cyclopropyl)(hydroxy)propylamino, morpholinylethyl-amino,oxopyrrolidinylmethylamino, ethyloxadiazolylamino,methylthiadiazolylamino, thiazolylmethylamino, thiazolylethylamino,pyrimidinylmethylamino, methylpyrazolyl-methylamino, acetylamino,N-acetyl-N-methylamino, N-isopropylcarbonyl-N-methylamino,acetylaminomethyl, ethenylcarbonylamino, bis(ethenylcarbonyl)amino,N-cyclopropylcarbonyl-N-methylamino, methoxycarbonylamino,ethoxycarbonylamino, tert-butoxycarbonylamino,methoxycarbonylethylamino, ethylaminocarbonylamino,butylaminocarbonylamino, methylsulphonylamino,N-methyl-N-(methylsulphonyl)amino, bis(methylsulphonyl)amino,N-(carboxymethyl)-N-methylamino, N-(carboxyethyl)-N-methylamino,carboxycyclopentylamino, carboxycyclopropylmethylamino, formyl, acetyl,isopropylcarbonyl, cyclobutylcarbonyl, phenylcarbonyl, acetoxyisopropyl,carboxy, carboxymethyl, carboxyethyl, methoxycarbonyl, ethoxycarbonyl,n-butoxycarbonyl, tert-butoxycarbonyl, methoxycarbonylmethyl,ethoxycarbonylmethyl, ethoxycarbonylethyl, morpholinylethoxycarbonyl,ethoxycarbonylmethylidenyl, methylsulphonylaminocarbonyl,acetylaminosulphonyl, methoxyaminocarbonyl, tetrazolyl,tetrazolylmethyl, hydroxyoxadiazolyl, aminocarbonyl,methylaminocarbonyl, hydroxyethylaminocarbonyl, dimethylaminocarbonyl,aminocarbonylmethyl, aminosulphonyl, methylaminosulphonyl,dimethylaminosulphonyl, methylsulphoximinyl and(methyl)(N-methyl)sulphoximinyl.

Generally, R¹¹ represents C₁₋₆ alkyl, C₂₋₆ alkynyl, aryl, C₃₋₇heterocycloalkyl, C₃₋₇ heterocycloalkenyl, heteroaryl,(C₃₋₇)heterocycloalkyl(C₁₋₆)alkyl-aryl-, heteroaryl-(C₃₋₇)hetero cycloalkyl-, (C₃₋₇)cyclo alkyl-hetero aryl-,(C₃₋₇)cycloalkyl(C₁₋₆)alkyl-heteroaryl-, (C₄₋₇)cycloalkenyl-heteroaryl-,(C₄₋₉) bicycloalkyl-heteroaryl-, (C₃₋₇)heterocycloalkyl-heteroaryl-,(C₃₋₇)hetero cyclo alkyl(C₁₋₆)alkyl-hetero aryl-,(C₃₋₇)heterocycloalkenyl-heteroaryl-,(C₄₋₉)heterobicycloalkyl-heteroaryl- or(C₄₋₉)spiroheterocycloalkyl-heteroaryl-, any of which groups may beoptionally substituted by one or more substituents.

More typically, R¹¹ represents hydrogen, halogen or —OR^(a); or R¹¹represents heteroaryl or (C₃₋₇)cycloalkyl-heteroaryl-, either of whichgroups may be optionally substituted by one or more substituents.

More generally, R¹¹ represents hydrogen, halogen or —OR^(a); or R¹¹represents heteroaryl, which group may be optionally substituted by oneor more substituents.

In a first embodiment, R¹¹ represents hydrogen.

In a second embodiment, R¹¹ represents halogen. In one aspect of thatembodiment, R¹¹ represents bromo. In another aspect of that embodiment,R¹¹ represents chloro.

In a third embodiment, R¹¹ represents —OR^(a).

In a fourth embodiment, R¹¹ represents optionally substituted C₁₋₆alkyl. In one aspect of that embodiment, R¹¹ represents optionallysubstituted ethyl.

In a fifth embodiment, R¹¹ represents optionally substituted C₂₋₆alkynyl. In one aspect of that embodiment, R¹¹ represents optionallysubstituted butynyl.

In a sixth embodiment, R¹¹ represents optionally substituted aryl. Inone aspect of that embodiment, R¹¹ represents optionally substitutedphenyl.

In a seventh embodiment, R¹¹ represents optionally substituted C₃₋₇heterocycloalkyl.

In an eighth embodiment, R¹¹ represents optionally substituted C₃₋₇heterocycloalkenyl.

In a ninth embodiment, R¹¹ represents optionally substituted heteroaryl.In selected aspects of that embodiment, R¹¹ represents benzofuryl,thienyl, indolyl, pyrazolyl, indazolyl, isoxazolyl, thiazolyl,imidazolyl, pyridinyl, quinolinyl, pyridazinyl, pyrimidinyl orpyrazinyl, any of which groups may be optionally substituted by one ormore substituents.

In a tenth embodiment, R¹¹ represents optionally substituted(C₃₋₇)-heterocycloalkyl(C₁₋₆)alkyl-aryl-. In a first aspect of thatembodiment, R¹¹ represents optionally substitutedpyrrolidinylmethylphenyl-. In a second aspect of that embodiment, R¹¹represents optionally substituted piperazinylmethylphenyl-.

In an eleventh embodiment, R¹¹ represents optionally substitutedheteroaryl(C₃₋₇)-heterocycloalkyl-. In one aspect of that embodiment,R¹¹ represents optionally substituted pyridinylpiperazinyl-.

In a twelfth embodiment, R¹¹ represents optionally substituted(C₃₋₇)cycloalkyl-heteroaryl-. In a first aspect of that embodiment, R¹¹represents optionally substituted cyclohexylpyrazolyl-. In a secondaspect of that embodiment, R¹¹ represents optionally substitutedcyclohexylpyridinyl-. In a third aspect of that embodiment, R¹¹represents optionally substituted cyclopropylpyrimidinyl-. In a fourthaspect of that embodiment, R¹¹ represents optionally substitutedcyclobutylpyrimidinyl-. In a fifth aspect of that embodiment, R¹¹represents optionally substituted cyclopentylpyrimidinyl-. In a sixthaspect of that embodiment, R¹¹ represents optionally substitutedcyclohexylpyrimidinyl-. In a seventh aspect of that embodiment, R¹¹represents optionally substituted cyclohexylpyrazinyl-.

In a thirteenth embodiment, R¹¹ represents optionally substituted(C₄₋₇)cycloalkenyl-heteroaryl-.

In a fourteenth embodiment, R¹¹ represents optionally substituted(C₃₋₇)-heterocycloalkyl-heteroaryl-. In a first aspect of thatembodiment, R¹¹ represents optionally substitutedpyrrolidinylpyridinyl-. In a second aspect of that embodiment, R¹represents optionally substituted tetrahydropyranylpyridinyl-. In athird aspect of that embodiment, R¹¹ represents optionally substitutedpiperidinylpyridinyl-. In a fourth aspect of that embodiment, R¹¹represents optionally substituted piperazinylpyridinyl-. In a fifthaspect of that embodiment, R¹¹ represents optionally substitutedmorpholinylpyridinyl-. In a sixth aspect of that embodiment, R¹¹represents optionally substituted thiomorpholinylpyridinyl-. In aseventh aspect of that embodiment, R¹¹ represents optionally substituteddiazepanylpyridinyl-. In an eighth aspect of that embodiment, R¹¹represents optionally substituted oxetanylpyrimidinyl-. In a ninthaspect of that embodiment, R¹¹ represents optionally substitutedazetidinylpyrimidinyl-. In a tenth aspect of that embodiment, R¹¹represents optionally substituted tetrahydrofuranylpyrimidinyl-. In aneleventh aspect of that embodiment, R¹¹ represents optionallysubstituted pyrrolidinylpyrimidinyl-. In a twelfth aspect of thatembodiment, R¹¹ represents optionally substitutedtetrahydropyranylpyrimidinyl-. In a thirteenth aspect of thatembodiment, R¹¹ represents optionally substitutedpiperidinylpyrimidinyl-. In a fourteenth aspect of that embodiment, R¹¹represents optionally substituted piperazinylpyrimidinyl-. In afifteenth aspect of that embodiment, R¹¹ represents optionallysubstituted morpholinylpyrimidinyl-. In a sixteenth aspect of thatembodiment, R¹¹ represents optionally substitutedthiomorpholinylpyrimidinyl-. In a seventeenth aspect of that embodiment,R¹¹ represents optionally substituted azepanylpyrimidinyl-. In aneighteenth aspect of that embodiment, R¹¹ represents optionallysubstituted oxazepanylpyrimidinyl-. In a nineteenth aspect of thatembodiment, R¹¹ represents optionally substituteddiazepanylpyrimidinyl-. In a twentieth aspect of that embodiment, R¹¹represents optionally substituted thiadiazepanylpyrimidinyl-. In atwenty-first aspect of that embodiment, R¹¹ represents optionallysubstituted oxetanylpyrazinyl-. In a twenty-second aspect of thatembodiment, R¹¹ represents optionally substituted piperidinylpyrazinyl-.

In a fifteenth embodiment, R¹¹ represents optionally substituted(C₃₋₇)-heterocycloalkyl(C₁₋₆)alkyl-heteroaryl-. In a first aspect ofthat embodiment, R¹¹ represents optionally substitutedmorpholinylmethylthienyl-. In a second aspect of that embodiment, R¹¹represents optionally substituted morpholinylethylpyrazolyl-.

In a sixteenth embodiment, R¹¹ represents optionally substituted(C₃₋₇)-heterocycloalkenyl-heteroaryl-.

In a seventeenth embodiment, R¹¹ represents optionally substituted(C₄₋₉)-heterobicycloalkyl-heteroaryl-.

In an eighteenth embodiment, R¹¹ represents optionally substituted(C₄₋₉)-spiroheterocycloalkyl-heteroaryl-.

In a nineteenth embodiment, R¹¹ represents optionally substituted(C₃₋₇)-cycloalkyl(C₁₋₆)alkyl-heteroaryl-. In one aspect of thatembodiment, R¹¹ represents optionally substitutedcyclohexylmethylpyrimidinyl-.

In a twentieth embodiment, R¹¹ represents optionally substituted(C₄₋₉)-bicycloalkyl-heteroaryl-.

Appositely, R¹¹ represents hydrogen, chloro, bromo or —OR^(a); or R¹¹represents ethyl, butynyl, phenyl, pyrrolidinyl, piperidinyl,piperazinyl, morpholinyl, 1,2,3,6-tetrahydropyridinyl, benzofuryl,thienyl, indolyl, pyrazolyl, indazolyl, isoxazolyl, thiazolyl,imidazolyl, pyridinyl, quinolinyl, pyridazinyl, pyrimidinyl, pyrazinyl,pyrrolidinylmethylphenyl, piperazinylmethylphenyl, pyridinylpiperazinyl,cyclohexylpyrazolyl, cyclohexylpyridinyl, cyclopropylpyrimidinyl,cyclobutylpyrimidinyl, cyclopentylpyrimidinyl, cyclohexylpyrimidinyl,cyclohexylpyrazinyl, cyclohexylmethylpyrimidinyl, cyclohexenylpyridinyl,cyclohexenylpyrimidinyl, bicyclo[3.1.0]hexanylpyridinyl,bicyclo[3.1.0]hexanylpyrimidinyl, bicyclo[4.1.0]heptanylpyrimidinyl,bicyclo[2.2.2]octanylpyrimidinyl, pyrrolidinylpyridinyl,tetrahydropyranylpyridinyl, piperidinylpyridinyl, piperazinylpyridinyl,morpholinylpyridinyl, thiomorpholinylpyridinyl, diazepanylpyridinyl,oxetanylpyrimidinyl, azetidinylpyrimidinyl,tetrahydrofuranylpyrimidinyl, pyrrolidinylpyrimidinyl,tetrahydropyranylpyrimidinyl, piperidinylpyrimidinyl,piperazinylpyrimidinyl,hexahydro-[1,2,5]thiadiazolo[2,3-a]-pyrazinylpyrimidinyl,morpholinylpyrimidinyl, thiomorpholinylpyrimidinyl, azepanylpyrimidinyl,oxazepanylpyrimidinyl, diazepanylpyrimidinyl, thiadiazepanylpyrimidinyl,oxetanylpyrazinyl, piperidinylpyrazinyl, morpholinylmethylthienyl,morpholinylethylpyrazolyl, 3-azabicyclo[3.1.0]hexanylpyridinyl,3-azabicyclo[3.1.0]hexanylpyridazinyl,3-azabicyclo[3.1.0]hexanylpyrimidinyl,2-oxa-5-azabicyclo[2.2.1]heptanylpyrimidinyl,3-azabicyclo[3.1.1]heptanylpyrimidinyl,3-azabicyclo[4.1.0]heptanylpyridinyl,3-azabicyclo[4.1.0]heptanylpyrimidinyl,2-oxabicyclo[2.2.2]octanylpyrimidinyl,3-azabicyclo[3.2.1]octanylpyrimidinyl,8-azabicyclo[3.2.1]octanylpyrimidinyl,3-oxa-8-azabicyclo[3.2.1]octanylpyrimidinyl,3,6-diazabicyclo[3.2.2]nonanylpyrimidinyl,3-oxa-7-azabicyclo[3.3.1]nonanylpyrimidinyl,5-azaspiro[2.3]hexanylpyrimidinyl, 5-azaspiro[2.4]heptanylpyrimidinyl,2-azaspiro[3.3]heptanylpyrimidinyl,2-oxa-6-azaspiro[3.3]heptanylpyrimidinyl,2-oxa-6-azaspiro[3.4]octanylpyrimidinyl,2-oxa-6-azaspiro[3.5]nonanylpyrimidinyl,2-oxa-7-azaspiro[3.5]nonanylpyrimidinyl or2,4,8-triazaspiro[4.5]decanylpyrimidinyl, any of which groups may beoptionally substituted by one or more substituents.

More particularly, R¹¹ represents hydrogen, chloro or —OR^(a); or R¹¹represents pyrazolyl, pyridinyl, pyrimidinyl or cyclobutylpyrimidinyl,any of which groups may be optionally substituted by one or moresubstituents.

Illustratively, R¹¹ represents hydrogen, chloro or —OR^(a); or R¹¹represents pyrazolyl or pyridinyl, either of which groups may beoptionally substituted by one or more substituents.

Typical examples of optional substituents on R¹¹ include one, two orthree substituents independently selected from halogen, halo(C₁₋₆)alkyl,cyano, cyano(C₁₋₆)alkyl, nitro(C₁₋₆)alkyl, C₁₋₆ alkyl, trifluoromethyl,trifluoroethyl, C₂₋₆ alkenyl, hydroxy, hydroxy(C₁₋₆)alkyl, C₁₋₆ alkoxy,trifluoroethoxy, earboxy(C₃₋₇)cycloalkyloxy, C₁₋₆ alkylthio, C₁₋₆alkylsulphonyl, (C₁₋₆)alkylsulphonyl(C₁₋₆)alkyl, oxo, amino,amino-(C₁₋₆)alkyl, C₁₋₆ alkylamino, di(C₁₋₆)alkylamino,(C₁₋₆)alkoxy(C₁₋₆)alkylamino,N—[(C₁₋₆)alkyl]-N-[hydroxy(C₁₋₆)alkyl]amino,(C₂₋₆)alkylcarbonylamino(C₁₋₆)alkyl, C₁₋₆ alkylsulphonylamino,N—[(C₁₋₆)alkyl]-N—[(C₁₋₆)alkylsulphonyl]amino,bis[(C₁₋₆)alkylsulphonyl]amino,N—[(C₁₋₆)alkyl]-N-[carboxy(C₁₋₆)alkyl]amino,carboxy(C₃₋₇)cycloalkylamino, carboxy(C₃₋₇)cycloalkyl(C₁₋₆)alkylamino,formyl, C₂₋₆ alkylcarbonyl, (C₂₋₆)alkylcarbonyloxy(C₁₋₆)alkyl, carboxy,carboxy(C₁₋₆)alkyl, C₂₋₆ alkoxycarbonyl, C₂₋₆ alkoxycarbonyl(C₁₋₆)alkyl,morpholinyl(C₁₋₆)alkoxycarbonyl, C₂₋₆ alkoxycarbonyl-methylidenyl, acarboxylic acid isostere or prodrug moiety Ω as defined herein,—(C₁₋₆)alkyl-Ω, aminocarbonyl, aminosulphonyl, (C₁₋₆)alkylsulphoximinyland [(C₁₋₆)alkyl][N—(C₁₋₆)alkyl]sulphoximinyl.

Selected examples of optional substituents on R¹¹ include one, two orthree substituents independently selected from C₁₋₆ alkyl, hydroxy,hydroxy(C₁₋₆)alkyl and (C₁₋₆)alkylsulphoximinyl.

Suitable examples of optional substituents on R¹¹ include one, two orthree substituents independently selected from C₁₋₆ alkyl.

Typical examples of particular substituents on R¹¹ include one, two orthree substituents independently selected from fluoro, chloro,fluoromethyl, fluoroisopropyl, cyano, cyanoethyl, nitromethyl, methyl,ethyl, isopropyl, trifluoromethyl, trifluoroethyl, ethenyl, hydroxy,hydroxymethyl, hydroxyisopropyl, methoxy, isopropoxy, trifluoroethoxy,carboxycyclobutyloxy, methylthio, methylsulphonyl, methylsulphonylethyl,oxo, amino, aminomethyl, aminoisopropyl, methylamino, dimethylamino,methoxyethylamino, N-(hydroxyethyl)-N-(methyl)amino, acetylaminomethyl,methylsulphonylamino, N-methyl-N-(methylsulphonyl)amino,bis(methylsulphonyl)amino, N-(carboxyethyl)-N-(methyl)amino,carboxycyclopentylamino, carboxycyclopropylmethylamino, formyl, acetyl,acetoxyisopropyl, carboxy, carboxymethyl, carboxyethyl, methoxycarbonyl,ethoxycarbonyl, n-butoxycarbonyl, tert-butoxycarbonyl,methoxycarbonylmethyl, ethoxycarbonylmethyl, ethoxycarbonylethyl,morpholinylethoxycarbonyl, ethoxycarbonylmethylidenyl,methylsulphonylaminocarbonyl, acetylaminosulphonyl,methoxyaminocarbonyl, tetrazolyl, tetrazolylmethyl, hydroxyoxadiazolyl,aminocarbonyl, aminosulphonyl, methylsulphoximinyl and(methyl)(N-methyl)sulphoximinyl.

Selected examples of particular substituents on R¹¹ include one, two orthree substituents independently selected from methyl, hydroxy,hydroxyisopropyl and methylsulphoximinyl.

Suitable examples of particular substituents on R¹¹ include one, two orthree substituents independently selected from methyl.

In a particular embodiment, R¹¹ is substituted by hydroxy(C₁₋₆)alkyl. Inone aspect of that embodiment, R¹¹ is substituted by hydroxyisopropyl,especially 2-hydroxyprop-2-yl.

Selected values of R¹¹ include hydrogen, chloro, bromo, —OR^(a),methoxycarbonylethyl, ethoxycarbonylethyl, hydroxybutynyl, chlorophenyl,hydroxyphenyl, methylsulphonylphenyl, aminomethylphenyl,aminoisopropylphenyl, acetylaminomethylphenyl, acetylphenyl,methoxycarbonylphenyl, aminocarbonylphenyl, aminosulphonylphenyl,acetylaminosulphonylphenyl, (methoxycarbonyl)(methyl)pyrrolidinyl,oxopiperidinyl, ethoxycarbonylpiperidinyl, methylsulphonylpiperazinyl,morpholinyl, methylsulphonyl-1,2,3,6-tetrahydropyridinyl,acetyl-1,2,3,6-tetrahydropyridinyl,tert-butoxycarbonyl-1,2,3,6-tetrahydropyridinyl,methoxycarbonylmethyl-1,2,3,6-tetrahydropyridinyl, benzofuryl, thienyl,indolyl, pyrazolyl, methylpyrazolyl, dimethylpyrazolyl,(methyl)[N-methyl-N-(methylsulfonyl)amino]pyrazolyl, methylindazolyl,dimethylisoxazolyl, hydroxyisopropylthiazolyl, methylimidazolyl,dimethylimidazolyl, pyridinyl, fluoropyridinyl, cyanopyridinyl,methylpyridinyl, (cyano)(methyl)pyridinyl, dimethylpyridinyl,trifluoromethylpyridinyl, ethenylpyridinyl, hydroxyisopropylpyridinyl,methoxypyridinyl, (methoxy)(methyl)pyridinyl, isopropoxypyridinyl,trifluoroethoxypyridinyl, (methyl)-(trifluoroethoxy)pyridinyl,methylsulphonylpyridinyl, oxopyridinyl, (methyl)(oxo)-pyridinyl,(dimethyl)(oxo)pyridinyl, aminopyridinyl, methylaminopyridinyl,dimethylaminopyridinyl, methoxyethylaminopyridinyl,N-(hydroxyethyl)-N-(methyl)aminopyridinyl,methylsulphonylaminopyridinyl, [bis(methylsulphonyl)amino]pyridinyl,carboxypyridinyl, quinolinyl, hydroxypyridazinyl, pyrimidinyl,fluoroisopropylpyrimidinyl, hydroxyisopropylpyrimidinyl,methoxypyrimidinyl, carboxycyclobutyloxypyrimidinyl,methylthiopyrimidinyl, methylsulphonylpyrimidinyl, oxopyrimidinyl,aminopyrimidinyl, dimethylaminopyrimidinyl,methoxyethylaminopyrimidinyl, N-(c arboxyethyl)-N-(methyl)aminopyrimidinyl, carboxycyclopentylaminopyrimidinyl,carboxycyclopropylmethylaminopyrimidinyl, acetoxyisopropylpyrimidinyl,ethoxycarbonylethylpyrimidinyl, hydroxypyrazinyl,hydroxyisopropylpyrazinyl, pyrrolidinylmethylphenyl,piperazinylmethylphenyl, pyridinylpiperazinyl,carboxycyclohexylpyrazolyl, carboxycyclohexylpyridinyl,fluoromethylcyclopropylpyrimidinyl,acetylaminomethylcyclopropylpyrimidinyl, hydroxycyclobutylpyrimidinyl,carboxycyclopentylpyrimidinyl, carboxycyclohexylpyrimidinyl,(carboxy)(methyl)cyclohexylpyrimidinyl,(carboxy)(hydroxy)cyclohexylpyrimidinyl,carboxymethylcyclohexylpyrimidinyl, ethoxycarbonylcyclohexylpyrimidinyl,(methoxycarbonyl)(methyl)-cyclohexylpyrimidinyl,(ethoxycarbonyl)(methyl)cyclohexylpyrimidinyl,carboxycyclohexylpyrazinyl, carboxycyclohexylmethylpyrimidinyl,carboxycyclohexenylpyridinyl, carboxycyclohexenylpyrimidinyl,ethoxycarbonylcyclohexenylpyrimidinyl,carboxybicyclo[3.1.0]hexanylpyridinyl,carboxybicyclo[3.1.0]hexanylpyrimidinyl,ethoxycarbonylbicyclo[3.1.0]hexanylpyrimidinyl,carboxybicyclo[4.1.0]heptanylpyrimidinyl,carboxybicyclo[2.2.2]octanylpyrimidinyl, pyrrolidinylpyridinyl,hydroxypyrrolidinylpyridinyl, hydroxytetrahydropyranylpyridinyl, piperidinylpyridinyl, acetylpiperidinylpyridinyl,(carboxy)(methyl)piperidinylpyridinyl,[(carboxy)(methyl)-piperidinyl](fluoro)pyridinyl,[(carboxy)(methyl)piperidinyl](chloro)pyridinyl, piperazinylpyridinyl,(methyl)(piperazinyl)pyridinyl, cyanoethylpiperazinylpyridinyl,trifluoroethylpiperazinylpyridinyl, methylsulphonylpiperazinylpyridinyl,methylsulphonylethylpiperazinylpyridinyl, oxopiperazinylpyridinyl,acetylpiperazinylpyridinyl,(tert-butoxycarbonylpiperazinyl)(methyl)pyridinyl,carboxymethylpiperazinylpyridinyl, carboxyethylpiperazinylpyridinyl,ethoxycarbonylmethylpiperazinylpyridinyl,ethoxycarbonylethylpiperazinylpyridinyl, morpholinylpyridinyl,thiomorpholinylpyridinyl, oxothiomorpholinylpyridinyl,dioxothiomorpholinylpyridinyl, oxodiazepanylpyridinyl,fluorooxetanylpyrimidinyl, hydroxyoxetanylpyrimidinyl,hydroxyazetidinylpyrimidinyl, (hydroxy)(methyl)azetidinylpyrimidinyl,carboxyazetidinylpyrimidinyl,(tert-butoxycarbonyl)(hydroxy)azetidinylpyrimidinyl,tetrazolylazetidinylpyrimidinyl, hydroxytetrahydrofuranylpyrimidinyl,hydroxypyrrolidinylpyrimidinyl, carboxypyrrolidinylpyrimidinyl,(carboxy)(methyl)pyrrolidinylpyrimidinyl,carboxymethylpyrrolidinylpyrimidinyl,ethoxycarbonylpyrrolidinylpyrimidinyl,fluorotetrahydropyranylpyrimidinyl, hydroxytetrahydropyranylpyrimidinyl,difluoropiperidinylpyrimidinyl, (cyano)(methyl)piperidinylpyrimidinyl,(hydroxy)(nitromethyl)piperidinylpyrimidinyl,(hydroxy)(methyl)piperidinylpyrimidinyl,(hydroxy)(trifluoromethyl)-piperidinylpyrimidinyl,(hydroxymethyl)(methyl)piperidinylpyrimidinyl,methylsulphonylpiperidinylpyrimidinyl, oxopiperidinylpyrimidinyl,(formyl)(methyl)-piperidinylpyrimidinyl, carboxypiperidinylpyrimidinyl,(carboxy)(fluoro)piperidinylpyrimidinyl,(carboxy)(methyl)piperidinylpyrimidinyl,(carboxy)(ethyl)piperidinylpyrimidinyl,(carboxy)(trifluoromethyl)piperidinylpyrimidinyl,(carboxy)(hydroxy)-piperidinylpyrimidinyl,(carboxy)(hydroxymethyl)piperidinylpyrimidinyl,(carboxy)-(methoxy)piperidinylpyrimidinyl,(amino)(carboxy)piperidinylpyrimidinyl,carboxymethylpiperidinylpyrimidinyl,methoxycarbonylpiperidinylpyrimidinyl,ethoxycarbonylpiperidinylpyrimidinyl,(ethoxycarbonyl)(fluoro)piperidinylpyrimidinyl,(methoxycarbonyl)(methyl)piperidinylpyrimidinyl,(ethyl)(methoxycarbonyl)piperidinylpyrimidinyl,(isopropyl)(methoxycarbonyl)piperidinylpyrimidinyl,(ethoxycarbonyl)-(methyl)piperidinylpyrimidinyl,(n-butoxycarbonyl)(methyl)piperidinylpyrimidinyl,(ethoxycarbonyl)(trifluoromethyl)piperidinylpyrimidinyl,(ethoxycarbonyl)-(hydroxymethyl)piperidinylpyrimidinyl,(methoxy)(methoxycarbonyl)piperidinylpyrimidinyl,(carboxy)(methoxycarbonyl)piperidinylpyrimidinyl,(methyl)-(morpholinylethoxycarbonyl)piperidinylpyrimidinyl,ethoxycarbonylmethylpiperidinylpyrimidinyl,methylsulphonylaminocarbonylpiperidinylpyrimidinyl,acetylaminosulphonylpiperidinylpyrimidinyl,methoxyaminocarbonylpiperidinylpyrimidinyl,tetrazolylpiperidinylpyrimidinyl,hydroxyoxadiazolylpiperidinylpyrimidinyl,aminosulphonylpiperidinylpyrimidinyl, piperazinylpyrimidinyl,methylsulphonylpiperazinylpyrimidinyl, oxopiperazinylpyrimidinyl,carboxypiperazinylpyrimidinyl, carboxyethylpiperazinylpyrimidinyl,tert-butoxycarbonylpiperazinylpyrimidinyl,tetrazolylmethylpiperazinylpyrimidinyl,trioxohexahydro-[1,2,5]thiadiazolo[2,3-a]pyrazinylpyrimidinyl,morpholinylpyrimidinyl, dimethylmorpholinylpyrimidinyl,hydroxymethylmorpholinylpyrimidinyl, carboxymorpholinylpyrimidinyl,(carboxy)(methyl)morpholinylpyrimidinyl,carboxymethylmorpholinylpyrimidinyl, thiomorpholinylpyrimidinyl,dioxothiomorpholinylpyrimidinyl, carboxyazepanylpyrimidinyl,carboxyoxazepanylpyrimidinyl, oxodiazepanylpyrimidinyl,(oxodiazepanyl)(trifluoromethyl)pyrimidinyl,(oxodiazepanyl)(methoxy)pyrimidinyl, (methyl)(oxo)diazepanylpyrimidinyl,dioxothiadiazepanylpyrimidinyl, hydroxyoxetanylpyrazinyl,(carboxy)(methyl)piperidinylpyrazinyl,(ethoxycarbonyl)(methyl)piperidinylpyrazinyl, morpholinylmethylthienyl,morpholinylethylpyrazolyl, carboxy-3-azabicyclo[3.1.0]hexanylpyridinyl,carboxy-3-azabicyclo[3.1.0]hexanylpyridazinyl,carboxy-3-azabicyclo[3.1.0]hexanylpyrimidinyl,(carboxy)(methyl)-3-azabicyclo[3.1.0]hexanylpyrimidinyl,methoxycarbonyl-3-azabicyclo[3.1.0]hexanylpyrimidinyl,ethoxycarbonyl-3-azabicyclo[3.1.0]hexanylpyrimidinyl,2-oxa-5-azabicyclo[2.2.1]heptanylpyrimidinyl,carboxy-2-oxa-5-azabicyclo-[2.2.1]heptanylpyrimidinyl,carboxy-3-azabicyclo[3.1.1]heptanylpyrimidinyl,carboxy-3-azabicyclo[4.1.0]heptanylpyridinyl,carboxy-3-azabicyclo[4.1.0]heptanylpyrimidinyl,methoxycarbonyl-3-azabicyclo[4.1.0]heptanylpyrimidinyl,ethoxycarbonyl-3-azabicyclo-[4.1.0]heptanylpyrimidinyl,(hydroxy)(methyl)(oxo)-2-oxabicyclo[2.2.2]octanylpyrimidinyl,carboxy-3-azabicyclo[3.2.1]octanylpyrimidinyl,methoxycarbonyl-3-azabicyclo[3.2.1]octanylpyrimidinyl,oxo-8-azabicyclo[3.2.1]octanylpyrimidinyl,ethoxycarbonylmethylidenyl-8-azabicyclo[3.2.1]octanylpyrimidinyl,3-oxa-8-azabicyclo-[3.2.1]octanylpyrimidinyl,oxo-3,6-diazabicyclo[3.2.2]nonanylpyrimidinyl,carboxy-3-oxa-7-azabicyclo[3.3.1]nonanylpyrimidinyl,carboxy-5-azaspiro[2.3]hexanylpyrimidinyl,(carboxy)(methyl)-5-azaspiro[2.3]hexanylpyrimidinyl,carboxy-5-azaspiro[2.4]heptanylpyrimidinyl,carboxy-2-azaspiro[3.3]heptanylpyrimidinyl,2-oxa-6-azaspiro[3.3]heptanylpyrimidinyl,2-oxa-6-azaspiro[3.4]octanylpyrimidinyl,2-oxa-6-azaspiro[3.5]nonanylpyrimidinyl,2-oxa-7-azaspiro[3.5]nonanylpyrimidinyl and(dioxo)(methyl)-2,4,8-triazaspiro[4.5]decanylpyrimidinyl. Additionalvalues include methylsulphoximinylpyridinyl and(dihydroxy)(methyl)cyclobutylpyrimidinyl.

Typical values of R¹¹ include hydrogen, chloro, —OR^(a),methylpyrazolyl, pyridinyl, methylsulphoximinylpyridinyl,hydroxyisopropylpyrimidinyl and(dihydroxy)(methyl)-cyclobutylpyrimidinyl.

Illustrative values of R¹¹ include hydrogen, chloro, —OR^(a),methylpyrazolyl and pyridinyl.

Typical examples of optional substituents on R¹² include C₂₋₆alkoxycarbonyl.

Typical examples of particular substituents on R¹² includeethoxycarbonyl.

In a first embodiment, R¹² represents hydrogen. In a second embodiment,R¹² represents halogen. In one aspect of that embodiment, R¹² representsfluoro. In another aspect of that embodiment, R¹² represents chloro. Ina third embodiment, R¹² represents trifluoromethyl. In a fourthembodiment, R¹² represents optionally substituted C₁₋₆ alkyl. In oneaspect of that embodiment, R¹² represents unsubstituted methyl. Inanother aspect of that embodiment, R¹² represents unsubstituted ethyl.In a further aspect of that embodiment, R¹² represents monosubstitutedmethyl or monosubstituted ethyl.

Typical values of R¹² include hydrogen, fluoro, chloro, trifluoromethyl,methyl and ethoxycarbonylethyl.

Typically, R¹⁵ and R¹⁶ may independently represent hydrogen, fluoro,chloro, bromo, cyano, nitro, methyl, isopropyl, trifluoromethyl,hydroxy, methoxy, difluoromethoxy, trifluoromethoxy, methylthio,methylsulfinyl, methylsulfonyl, amino, methylamino, tert-butylamino,dimethylamino, phenylamino, acetylamino, methylsulfonylamino, formyl,acetyl, cyclopropylcarbonyl, azetidinylcarbonyl, pyrrolidinylcarbonyl,piperidinylcarbonyl, piperazinylcarbonyl, morpholinylcarbonyl, carboxy,methoxycarbonyl, aminocarbonyl, methylaminocarbonyl,dimethylaminocarbonyl, aminosulfonyl, methylaminosulfonyl anddimethylaminosulfonyl.

Typical values of R¹⁵ include hydrogen, halogen, C₁₋₆ alkyl,trifluoromethyl, C₁₋₆ alkoxy, difluoromethoxy and trifluoromethoxy.

Suitable values of R¹⁵ include hydrogen, halogen, C₁₋₆ alkyl anddifluoromethoxy.

Illustrative values of R¹⁵ include hydrogen, halogen and C₁₋₆ alkyl.

In a first embodiment, R¹⁵ represents hydrogen. In a second embodiment,R¹⁵ represents halogen. In a first aspect of that embodiment, R¹⁵represents fluoro. In a second aspect of that embodiment, R¹⁵ representschloro. In a third aspect of that embodiment, R¹⁵ represents bromo. In athird embodiment, R¹⁵ represents C₁₋₆ alkyl. In one aspect of thatembodiment, R¹⁵ represents methyl. In a fourth embodiment, R¹⁵represents trifluoromethyl. In a fifth embodiment, R¹⁵ represents C₁₋₆alkoxy. In one aspect of that embodiment, R¹⁵ represents methoxy. In asixth embodiment, R¹⁵ represents difluoromethoxy. In a seventhembodiment, R¹⁵ represents trifluoromethoxy.

Selected values of R¹⁵ include hydrogen, fluoro, chloro, methyl,trifluoromethyl, methoxy, difluoromethoxy and trifluoromethoxy.Additional values include bromo.

Representative values of R¹⁵ include hydrogen, fluoro, chloro, bromo,methyl and difluoromethoxy.

Particular values of R¹⁵ include hydrogen, chloro and methyl.

Typical values of R¹⁶ include hydrogen, halogen, cyano, C₁₋₆ alkyl,trifluoromethyl, difluoromethoxy and amino.

Suitable values of R¹⁶ include hydrogen, halogen, C₁₋₆ alkyl anddifluoromethoxy.

Illustrative values of R¹⁶ include hydrogen, halogen and C₁₋₆ alkyl.

In a first embodiment, R¹⁶ represents hydrogen. In a second embodiment,R¹⁶ represents halogen. In a first aspect of that embodiment, R¹⁶represents fluoro. In a second aspect of that embodiment, R¹⁶ representschloro. In a third aspect of that embodiment, R¹⁶ represents bromo. In athird embodiment, R¹⁶ represents cyano. In a fourth embodiment, R¹⁶represents C₁₋₆ alkyl. In one aspect of that embodiment, R¹⁶ representsmethyl. In a fifth embodiment, R¹⁶ represents trifluoromethyl. In asixth embodiment, R¹⁶ represents difluoromethoxy. In a seventhembodiment, R¹⁶ represents amino.

Selected values of R¹⁶ include hydrogen, fluoro, chloro, cyano, methyl,trifluoromethyl, difluoromethoxy and amino.

Representative values of R¹⁶ include hydrogen, fluoro, chloro, bromo,methyl and difluoromethoxy.

Particular values of R¹⁶ include hydrogen, chloro and methyl.

In a particular embodiment, R¹⁶ is attached at the para-position of thephenyl ring relative to the integer R¹⁵.

A particular sub-group of the compounds of formula (IIA) above isrepresented by the compounds of formula (IIB) and N-oxides thereof, andpharmaceutically acceptable salts and solvates thereof, and glucuronidederivatives thereof, and co-crystals thereof:

wherein

V represents C—R²² or N;

R²¹ represents hydrogen, halogen, halo(C₁₋₆)alkyl, cyano, C₁₋₆ alkyl,trifluoromethyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, hydroxy,hydroxy(C₁₋₆)alkyl, C₁₋₆ alkoxy, (C₁₋₆)alkoxy-(C₁₋₆)alkyl,difluoromethoxy, trifluoromethoxy, trifluoroethoxy,carboxy(C₃₋₇)cycloalkyl-oxy, C₁₋₆ alkylthio, C₁₋₆ alkylsulphonyl,(C₁₋₆)alkylsulphonyl(C₁₋₆)alkyl, amino, amino-(C₁₋₆)alkyl, C₁₋₆alkylamino, di(C₁₋₆)alkylamino, (C₁₋₆)alkoxy(C₁₋₆)alkylamino,N—[(C₁₋₆)-alkyl]-N-[hydroxy(C₁₋₆)alkyl]amino, C₂₋₆ alkylcarbonylamino,(C₂₋₆)alkylcarbonylamino-(C₁₋₆)alkyl, C₂₋₆ alkoxycarbonylamino,N—[(C₁₋₆)alkyl]-N-[carboxy(C₁₋₆)alkyl]amino,carboxy(C₃₋₇)cycloalkylamino, carboxy(C₃₋₇)cycloalkyl(C₁₋₆)alkylamino,C₁₋₆ alkylsulphonylamino, C₁₋₆ alkylsulphonylamino(C₁₋₆)alkyl, formyl,C₂₋₆ alkylcarbonyl, (C₂₋₆)alkylcarbonyloxy(C₁₋₆)alkyl, carboxy,carboxy(C₁₋₆)alkyl, C₂₋₆ alkoxycarbonyl,morpholinyl(C₁₋₆)alkoxycarbonyl, C₂₋₆ alkoxycarbonyl(C₁₋₆)alkyl, C₂₋₆alkoxycarbonyl-methylidenyl, aminocarbonyl, C₁₋₆ alkylaminocarbonyl,di(C₁₋₆)alkylaminocarbonyl, aminosulphonyl, C₁₋₆ alkylamino-sulphonyl,di(C₁₋₆)alkylamino-sulphonyl, (C₁₋₆)alkylsulphoximinyl or[(C₁₋₆)alkyl][N—(C₁₋₆)alkyl]sulphoximinyl; or R²¹ represents(C₃₋₇)cycloalkyl, (C₃₋₇)cycloalkyl(C₁₋₆)alkyl, (C₄₋₇)cycloalkenyl,(C₄₋₉)bicycloalkyl, (C₃₋₇)heterocycloalkyl, (C₃₋₇)heterocycloalkenyl,(C₄₋₉)heterobicycloalkyl or (C₄₋₉)spiroheterocycloalkyl, any of whichgroups may be optionally substituted by one or more substituents;

R²² represents hydrogen, halogen or C₁₋₆ alkyl;

R²³ represents hydrogen, C₁₋₆ alkyl, trifluoromethyl or C₁₋₆ alkoxy; and

E, Q, Z, R¹², R¹⁵ and R¹⁶ are as defined above.

In one embodiment, V represents C—R²². In another embodiment, Vrepresents N.

Typically, R²¹ represents hydrogen, halogen, halo(C₁₋₆)alkyl, cyano,C₁₋₆ alkyl, trifluoromethyl, C₂₋₆ alkenyl, hydroxy, hydroxy(C₁₋₆)alkyl,C₁₋₆ alkoxy, trifluoroethoxy, carboxy(C₃₋₇)cycloalkyloxy, C₁₋₆alkylthio, C₁₋₆ alkylsulphonyl, amino, C₁₋₆ alkylamino,di(C₁₋₆)alkylamino, (C₁₋₆)alkoxy(C₁₋₆)alkylamino,N—[(C₁₋₆)alkyl]-N-[hydroxy(C₁₋₆)alkyl]-amino,N—[(C₁₋₆)alkyl]-N-[carboxy(C₁₋₆)alkyl]amino,carboxy(C₃₋₇)cycloalkylamino, carboxy(C₃₋₇)cycloalkyl(C₁₋₆)alkylamino,C₁₋₆ alkylsulphonylamino, (C₂₋₆)alkylcarbonyl-oxy(C₁₋₆)alkyl, carboxy,morpholinyl(C₁₋₆)alkoxycarbonyl, C₂₋₆ alkoxycarbonyl(C₁₋₆)alkyl or C₂₋₆alkoxycarbonylmethylidenyl; or R²¹ represents (C₃₋₇)cycloalkyl,(C₃₋₇)cycloalkyl-(C₁₋₆)alkyl, (C₄₋₇)cycloalkenyl, (C₄₋₉)bicycloalkyl,(C₃₋₇)heterocycloalkyl, (C₄₋₉)heterobicycloalkyl or(C₄₋₉)spiroheterocycloalkyl, any of which groups may be optionallysubstituted by one or more substituents. Additionally, R²¹ may represent(C₁₋₆)alkylsulphoximinyl.

More typically, R²¹ represents hydroxy(C₁₋₆)alkyl or(C₁₋₆)alkylsulphoximinyl; or R²¹ represents (C₃₋₇)cycloalkyl, whichgroup may be optionally substituted by one or more substituents.

Where R²¹ represents an optionally substituted (C₃₋₇)cycloalkyl group,typical values include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyland cycloheptyl, any of which groups may be optionally substituted byone or more substituents.

Where R²¹ represents an optionally substituted(C₃₋₇)cycloalkyl(C₁₋₆)alkyl group, a typical value is cyclohexylmethyl,which group may be optionally substituted by one or more substituents.

Where R²¹ represents an optionally substituted (C₄₋₇)cycloalkenyl group,typical values include cyclobutenyl, cyclopentenyl, cyclohexenyl andcycloheptenyl, any of which groups may be optionally substituted by oneor more substituents.

Where R²¹ represents an optionally substituted (C₄₋₉)bicycloalkyl group,typical values include bicyclo[3.1.0]hexanyl, bicyclo[4.1.0]heptanyl andbicyclo[2.2.2]octanyl, any of which groups may be optionally substitutedby one or more substituents.

Where R²¹ represents an optionally substituted (C₃₋₇)heterocycloalkylgroup, typical values include oxetanyl, azetidinyl, tetrahydrofuranyl,pyrrolidinyl, tetrahydropyranyl, piperidinyl, piperazinyl,hexahydro-[1,2,5]thiadiazolo[2,3-c]pyrazinyl, morpholinyl,thiomorpholinyl, azepanyl, oxazepanyl, diazepanyl and thiadiazepanyl,any of which groups may be optionally substituted by one or moresubstituents.

Where R²¹ represents an optionally substituted (C₃₋₇)heterocycloalkenylgroup, a typical value is optionally substituted1,2,3,6-tetrahydropyridinyl.

Where R²¹ represents an optionally substituted (C₄₋₉)heterobicycloalkylgroup, typical values include 3-azabicyclo[3.1.0]hexanyl,2-oxa-5-azabicyclo[2.2.1]heptanyl, 3-azabicyclo[3.1.1]heptanyl,3-azabicyclo[4.1.0]heptanyl, 2-oxabicyclo[2.2.2]octanyl, quinuclidinyl,2-oxa-5-azabicyclo[2.2.2]octanyl, 3-azabicyclo[3.2.1]octanyl,8-azabicyclo-[3.2.1]octanyl, 3-oxa-8-azabicyclo[3.2.1]octanyl,3,8-diazabicyclo[3.2.1]octanyl, 3,6-diazabicyclo[3.2.2]nonanyl,3-oxa-7-azabicyclo[3.3.1]nonanyl and 3,9-diazabicyclo-[4.2.1]nonanyl,any of which groups may be optionally substituted by one or moresubstituents.

Where R²¹ represents an optionally substituted(C₄₋₉)spiroheterocycloalkyl group, typical values include5-azaspiro[2.3]hexanyl, 5-azaspiro[2.4]heptanyl,2-azaspiro[3.3]-heptanyl, 2-oxa-6-azaspiro[3.3]heptanyl,2-oxa-6-azaspiro[3.4]octanyl, 2-oxa-6-azaspiro-[3.5]nonanyl,2-oxa-7-azaspiro[3.5]nonanyl and 2,4,8-triazaspiro[4.5]-decanyl, any ofwhich groups may be optionally substituted by one or more substituents.

Illustratively, R²¹ represents hydroxy, hydroxy(C₁₋₆)alkyl, methoxy,carboxycyclobutyloxy, methylthio, methylsulphonyl, methylamino,N-[carboxyethyl]-N-methylamino, carboxycyclopentylamino,carboxycyclopropylmethylamino or ethoxycarbonylethyl; or R²¹ representscyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexylmethyl,cyclohexenyl, bicyclo[3.1.0]hexanyl, bicyclo[4.1.0]heptanyl,bicyclo[2.2.2]-octanyl, oxetanyl, azetidinyl, tetrahydrofuranyl,pyrrolidinyl, tetrahydropyranyl, piperidinyl, piperazinyl,hexahydro-[1,2,5]thiadiazolo[2,3-a]pyrazinyl, morpholinyl,thiomorpholinyl, azepanyl, oxazepanyl, diazepanyl, thiadiazepanyl,3-azabicyclo[3.1.0]-hexanyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl,3-azabicyclo[3.1.1]heptanyl, 3-azabicyclo-[4.1.0]heptanyl,2-oxabicyclo[2.2.2]octanyl, 3-azabicyclo[3.2.1]octanyl,8-azabicyclo-[3.2.1]octanyl, 3-oxa-8-azabicyclo[3.2.1]octanyl,3,6-diazabicyclo[3.2.2]nonanyl, 3-oxa-7-azabicyclo[3.3.1]nonanyl,5-azaspiro[2.3]hexanyl, 5-azaspiro[2.4]heptanyl or2-azaspiro-[3.3]heptanyl, any of which groups may be optionallysubstituted by one or more substituents. Additionally, R²¹ may represent(C₁₋₆)alkylsulphoximinyl.

More particularly, R²¹ represents hydroxy(C₁₋₆)alkyl or(C₁₋₆)alkylsulphoximinyl; or R²¹ represents cyclobutyl, which group maybe optionally substituted by one or more substituents.

Examples of optional substituents which may be present on R²¹ includeone, two or three substituents independently selected from halogen,halo(C₁₋₆)alkyl, cyano, cyano-(C₁₋₆)alkyl, nitro, nitro(C₁₋₆)alkyl, C₁₋₆alkyl, trifluoromethyl, trifluoroethyl, C₂₋₆ alkenyl, hydroxy,hydroxy(C₁₋₆)alkyl, C₁₋₆ alkoxy, difluoromethoxy, trifluoromethoxy,trifluoroethoxy, C₁₋₆ alkylthio, C₁₋₆ alkylsulphonyl,(C₁₋₆)alkylsulphonyl(C₁₋₆)alkyl, oxo, amino, C₁₋₆ alkylamino,di(C₁₋₆)alkylamino, C₂₋₆ alkylcarbonylamino,(C₂₋₆)alkylcarbonylamino-(C₁₋₆)alkyl, C₂₋₆ alkoxycarbonylamino, C₁₋₆alkylsulphonylamino, formyl, C₂₋₆ alkylcarbonyl, carboxy,carboxy(C₁₋₆)alkyl, C₂₋₆ alkoxycarbonyl,morpholinyl-(C₁₋₆)alkoxycarbonyl, C₂₋₆ alkoxycarbonyl(C₁₋₆)alkyl, C₂₋₆alkoxycarbonylmethylidenyl, a carboxylic acid isostere or prodrug moietyΩ as defined herein, —(C₁₋₆)alkyl-Ω, aminocarbonyl, C₁₋₆alkylaminocarbonyl, di(C₁₋₆)alkylaminocarbonyl, aminosulphonyl,di(C₁₋₆)alkylamino-sulphonyl, (C₁₋₆)alkylsulphoximinyl and[(C₁₋₆)alkyl][N—(C₁₋₆)alkyl]-sulphoximinyl.

Typical examples of optional substituents on R²¹ include one, two orthree substituents independently selected from C₁₋₆ alkyl and hydroxy.

Suitable examples of particular substituents on R²¹ include one, two orthree substituents independently selected from fluoro, fluoromethyl,chloro, bromo, cyano, cyanomethyl, cyanoethyl, nitro, nitromethyl,methyl, ethyl, isopropyl, trifluoromethyl, trifluoroethyl, ethenyl,hydroxy, hydroxymethyl, methoxy, ethoxy, difluoromethoxy,trifluoromethoxy, trifluoroethoxy, methylthio, methylsulphonyl,methylsulphonylmethyl, methylsulphonylethyl, oxo, amino, methylamino,dimethylamino, acetylamino, acetylaminomethyl, methoxycarbonylamino,ethoxycarbonylamino, tert-butoxycarbonylamino, methylsulphonylamino,formyl, acetyl, carboxy, carboxymethyl, carboxyethyl, methoxycarbonyl,ethoxycarbonyl, n-butoxycarbonyl, tert-butoxycarbonyl,morpholinylethoxycarbonyl, methoxycarbonylmethyl, ethoxycarbonylmethyl,ethoxycarbonylethyl, ethoxycarbonylmethylidenyl, acetylaminosulphonyl,methoxyaminocarbonyl, tetrazolyl, tetrazolylmethyl, hydroxyoxadiazolyl,aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl,methylsulphonylaminocarbonyl, aminosulphonyl, methylaminosulphonyl,dimethylaminosulphonyl, methylsulphoximinyl and(methyl)(N-methyl)sulphoximinyl.

Typical examples of particular substituents on R²¹ include one, two orthree substituents independently selected from methyl and hydroxy.

Suitably, R²¹ represents hydrogen, fluoro, fluoroisopropyl, cyano,methyl, trifluoromethyl, ethenyl, hydroxy, hydroxyisopropyl, methoxy,isopropoxy, trifluoroethoxy, carboxycyclobutyloxy, methylthio,methylsulphonyl, amino, methylamino, dimethylamino, methoxyethylamino,N-(hydroxyethyl)-N-(methyl)amino, N-[carboxyethyl]-N-methylamino,carboxycyclopentylamino, carboxycyclopropylmethylamino,methylsulphonylamino, acetoxyisopropyl, carboxy, ethoxycarbonylethyl,fluoromethyl-cyclopropyl, acetylaminomethylcyclopropyl,hydroxycyclobutyl, carboxycyclopentyl, carboxycyclohexyl,(carboxy)(methyl)cyclohexyl, (carboxy)(hydroxy)cyclohexyl,carboxymethylcyclohexyl, ethoxycarbonylcyclohexyl,(methoxycarbonyl)(methyl)-cyclohexyl,(ethoxycarbonyl)(methyl)cyclohexyl, carboxycyclohexylmethyl,carboxy-cyclohexenyl, ethoxycarbonylcyclohexenyl,carboxybicyclo[3.1.0]hexanyl, ethoxycarbonylbicyclo[3.1.0]hexanyl,carboxybicyclo[4.1.0]heptanyl, carboxybicyclo-[2.2.2]octanyl,fluorooxetanyl, hydroxyoxetanyl, hydroxyazetidinyl,(hydroxy)(methyl)-azetidinyl, carboxyazetidinyl,(tert-butoxycarbonyl)(hydroxy)azetidinyl, tetrazolyl-azetidinyl,hydroxytetrahydrofuranyl, pyrrolidinyl, hydroxypyrrolidinyl,carboxy-pyrrolidinyl, (carboxy)(methyl)pyrrolidinyl,carboxymethylpyrrolidinyl, ethoxycarbonyl-pyrrolidinyl,fluorotetrahydropyranyl, hydroxytetrahydropyranyl, piperidinyl,difluoro-piperidinyl, (cyano)(methyl)piperidinyl,(hydroxy)(nitromethyl)piperidinyl, (hydroxy)-(methyl)piperidinyl,(hydroxy)(trifluoromethyl)piperidinyl,(hydroxymethyl)(methyl)-piperidinyl, methylsulphonylpiperidinyl,oxopiperidinyl, (formyl)(methyl)piperidinyl, acetylpiperidinyl,carboxypiperidinyl, (carboxy)(fluoro)piperidinyl,(carboxy)(methyl)-piperidinyl, (carboxy)(ethyl)piperidinyl,(carboxy)(trifluoromethyl)piperidinyl, (carboxy)-(hydroxy)piperidinyl,(carboxy)(hydroxymethyl)piperidinyl, (carboxy)(methoxy)-piperidinyl,(amino)(carboxy)piperidinyl, carboxymethylpiperidinyl,methoxycarbonyl-piperidinyl, (methoxycarbonyl)(methyl)piperidinyl,(ethyl)(methoxycarbonyl)piperidinyl,(isopropyl)(methoxycarbonyl)piperidinyl,(methoxy)(methoxycarbonyl)piperidinyl,(carboxy)(methoxycarbonyl)piperidinyl, ethoxycarbonylpiperidinyl,(ethoxycarbonyl)-(fluoro)piperidinyl,(ethoxycarbonyl)(methyl)piperidinyl,(ethoxycarbonyl)(trifluoromethyl)piperidinyl,(ethoxycarbonyl)(hydroxymethyl)piperidinyl,(n-butoxycarbonyl)-(methyl)piperidinyl,(methyl)(morpholinylethoxycarbonyl)piperidinyl,ethoxycarbonyl-methylpiperidinyl,methylsulphonylaminocarbonylpiperidinyl,acetylaminosulphonyl-piperidinyl, methoxyaminocarbonylpiperidinyl,tetrazolylpiperidinyl, hydroxyoxadiazolyl-piperidinyl,aminosulphonylpiperidinyl, piperazinyl, cyanoethylpiperazinyl,trifluoroethyl-piperazinyl, methylsulphonylpiperazinyl,methylsulphonylethylpiperazinyl, oxopiperazinyl, acetylpiperazinyl,carboxypiperazinyl, tert-butoxycarbonylpiperazinyl,carboxymethylpiperazinyl, carboxyethylpiperazinyl,ethoxycarbonylmethylpiperazinyl, ethoxycarbonylethylpiperazinyl,tetrazolylmethylpiperazinyl,trioxohexahydro-[1,2,5]thiadiazolo[2,3-c]pyrazinyl, morpholinyl,dimethylmorpholinyl, hydroxymethyl-morpholinyl, carboxymorpholinyl,(carboxy)(methyl)morpholinyl, carboxymethyl-morpholinyl,thiomorpholinyl, oxothiomorpholinyl, dioxothiomorpholinyl,carboxy-azepanyl, carboxyoxazepanyl, oxodiazepanyl,(methyl)(oxo)diazepanyl, dioxo-thiadiazepanyl,carboxy-3-azabicyclo[3.1.0]hexanyl,(carboxy)(methyl)-3-azabicyclo-[3.1.0]hexanyl,methoxycarbonyl-3-azabicyclo[3.1.0]hexanyl,ethoxycarbonyl-3-azabicyclo[3.1.0]hexanyl,2-oxa-5-azabicyclo[2.2.1]heptanyl,carboxy-2-oxa-5-azabicyclo[2.2.1]heptanyl,carboxy-3-azabicyclo[3.1.1]heptanyl,carboxy-3-azabicyclo-[4.1.0]heptanyl,methoxycarbonyl-3-azabicyclo[4.1.0]heptanyl,ethoxycarbonyl-3-azabicyclo[4.1.0]heptanyl,(hydroxy)(methyl)(oxo)-2-oxabicyclo[2.2.2]octanyl,carboxy-3-azabicyclo[3.2.1]octanyl,methoxycarbonyl-3-azabicyclo[3.2.1]octanyl,oxo-8-azabicyclo[3.2.1]octanyl,ethoxycarbonylmethylidenyl-8-azabicyclo[3.2.1]octanyl,3-oxa-8-azabicyclo[3.2.1]octanyl, oxo-3,6-diazabicyclo[3.2.2]nonanyl,carboxy-3-oxa-7-azabicyclo[3.3.1]nonanyl,carboxy-5-azaspiro[2.3]hexanyl,(carboxy)(methyl)-5-azaspiro-[2.3]hexanyl,carboxy-5-azaspiro[2.4]heptanyl, carboxy-2-azaspiro[3.3]heptanyl,2-oxa-6-azaspiro[3.3]heptanyl, 2-oxa-6-azaspiro[3.4]octanyl,2-oxa-6-azaspiro[3.5]nonanyl, 2-oxa-7-azaspiro[3.5]nonanyl or(dioxo)(methyl)-2,4,8-triazaspiro[4.5]decanyl. Additional values includemethylsulphoximinyl and (dihydroxy)(methyl)cyclobutyl.

Selected values of R²¹ include hydroxyisopropyl, methylsulphoximinyl and(dihydroxy)(methyl)cyclobutyl.

In a particular embodiment, R²¹ represents hydroxy(C₁₋₆)alkyl. In oneaspect of that embodiment, R²¹ represents hydroxyisopropyl, especially2-hydroxyprop-2-yl.

Generally, R²² represents hydrogen or C₁₋₆ alkyl.

Suitably, R²² represents hydrogen, chloro or methyl.

Typically, R²² represents hydrogen or methyl.

In one embodiment, R²² represents hydrogen. In another embodiment, R²²represents C₁₋₆ alkyl, especially methyl. In a further embodiment, R²²represents halogen. In one aspect of that embodiment, R²² representsfluoro. In another aspect of that embodiment, R²² represents chloro.

Generally, R²³ represents hydrogen or C₁₋₆ alkyl.

Suitably, R²³ represents hydrogen, methyl, trifluoromethyl or methoxy.

Typically, R²³ represents hydrogen or methyl.

In one embodiment, R²³ represents hydrogen. In another embodiment, R²³represents C₁₋₆ alkyl, especially methyl. In a further embodiment, R²³represents trifluoromethyl. In an additional embodiment, R²³ representsC₁₋₆ alkoxy, especially methoxy.

Particular sub-groups of the compounds of formula (IIB) above arerepresented by the compounds of formula (IIC), (IID), (IIE), (IIF),(IIG), (IIH), (Ill), (IIK) and (IIL), and N-oxides thereof, andpharmaceutically acceptable salts and solvates thereof, and glucuronidederivatives thereof, and co-crystals thereof:

wherein

T represents —CH₂— or —CH₂CH₂—;

U represents C(O) or S(O)₂;

W represents O, S, S(O), S(O)₂, S(O)(NR⁵), N(R³¹) or C(R³²)(R³³);

-M- represents —CH₂— or —CH₂CH₂—;

R³¹ represents hydrogen, cyano(C₁₋₆)alkyl, C₁₋₆ alkyl, trifluoromethyl,trifluoroethyl, C₁₋₆ alkylsulphonyl, (C₁₋₆)alkylsulphonyl(C₁₋₆)alkyl,formyl, C₂₋₆ alkylcarbonyl, carboxy, carboxy(C₁₋₆)alkyl, C₂₋₆alkoxycarbonyl, C₂₋₆ alkoxycarbonyl(C₁₋₆)alkyl, a carboxylic acidisostere or prodrug moiety Ω, —(C₁₋₆)alkyl-Ω, aminocarbonyl, C₁₋₆alkylaminocarbonyl, di(C₁₋₆)alkylaminocarbonyl, aminosulphonyl ordi(C₁₋₆)alkylamino-sulphonyl;

R³² represents hydrogen, halogen, cyano, hydroxy, hydroxy(C₁₋₆)alkyl,C₁₋₆ alkylsulphonyl, formyl, C₂₋₆ alkylcarbonyl, carboxy,carboxy(C₁₋₆)alkyl, C₂₋₆ alkoxycarbonyl, C₂₋₆ alkoxycarbonyl(C₁₋₆)alkyl,aminosulphonyl, (C₁₋₆)alkylsulphoximinyl,[(C₁₋₆)alkyl][N—(C₁₋₆)alkyl]sulphoximinyl, a carboxylic acid isostere orprodrug moiety Ω, or —(C₁₋₆)alkyl-Ω;

R³³ represents hydrogen, halogen, C₁₋₆ alkyl, trifluoromethyl, hydroxy,hydroxy-(C₁₋₆)alkyl, C₁₋₆ alkoxy, amino or carboxy;

R³⁴ represents hydrogen, halogen, halo(C₁₋₆)alkyl, hydroxy, C₁₋₆ alkoxy,C₁₋₆ alkylthio, C₁₋₆ alkylsulphinyl, C₁₋₆ alkylsulphonyl, amino, C₁₋₆alkylamino, di(C₁₋₆)alkylamino, (C₂₋₆)alkylcarbonylamino,(C₂₋₆)alkylcarbonylamino(C₁₋₆)alkyl, (C₁₋₆)alkylsulphonylamino or(C₁₋₆)alkylsulphonylamino(C₁₋₆)alkyl; and

V, E, Q, Z, R⁵, R¹², R¹⁵, R¹⁶, R²³ and Ω are as defined above.

In a first embodiment, T represents —CH₂—. In a second embodiment, Trepresents —CH₂CH₂—.

In a first embodiment, U represents C(O). In a second embodiment, Urepresents S(O)₂.

Generally, W represents O, S(O)₂, N(R³¹) or C(R³²)(R³³).

Typically, W represents O, N(R³¹) or C(R³²)(R³³).

In a first embodiment, W represents O. In a second embodiment, Wrepresents S. In a third embodiment, W represents S(O). In a fourthembodiment, W represents S(O)₂. In a fifth embodiment, W representsS(O)(NR⁵). In a sixth embodiment, W represents N(R³¹). In a seventhembodiment, W represents C(R³²)(R³³).

In one embodiment, -M- represents —CH₂—. In another embodiment, -M-represents —CH₂CH₂—.

Typically, R³¹ represents hydrogen, cyano(C₁₋₆)alkyl, C₁₋₆ alkyl,trifluoromethyl, trifluoroethyl, C₁₋₆ alkylsulphonyl,(C₁₋₆)alkylsulphonyl(C₁₋₆)alkyl, formyl, C₂₋₆ alkylcarbonyl, carboxy,carboxy(C₁₋₆)alkyl, C₂₋₆ alkoxycarbonyl, C₂₋₆alkoxycarbonyl-(C₁₋₆)alkyl, tetrazolyl(C₁₋₆)alkyl, aminocarbonyl, C₁₋₆alkylaminocarbonyl, di(C₁₋₆)alkylaminocarbonyl, aminosulphonyl, C₁₋₆alkylamino-sulphonyl or di(C₁₋₆)alkylamino-sulphonyl.

Typical values of R³¹ include hydrogen, cyanoethyl, methyl, ethyl,isopropyl, trifluoromethyl, trifluoroethyl, methylsulphonyl,methylsulphonylethyl, formyl, acetyl, carboxy, carboxymethyl,carboxyethyl, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl,ethoxycarbonylmethyl, ethoxycarbonylethyl, tetrazolylmethyl,aminocarbonyl, methylamino-carbonyl, dimethylaminocarbonyl,aminosulphonyl, methylaminosulphonyl and dimethylaminosulphonyl.

Generally, R³² represents halogen, carboxy, carboxy(C₁₋₆)alkyl, C₂₋₆alkoxycarbonyl, C₂₋₆ alkoxycarbonyl(C₁₋₆)alkyl, a carboxylic acidisostere or prodrug moiety Ω, or —(C₁₋₆)alkyl-Ω.

Typically, R³² represents hydrogen, halogen, cyano, hydroxy,hydroxy(C₁₋₆)alkyl, C₁₋₆ alkylsulphonyl, formyl, carboxy,carboxy(C₁₋₆)alkyl, C₂₋₆ alkoxycarbonyl, C₂₋₆ alkoxycarbonyl(C₁₋₆)alkyl,aminosulphonyl, (C₁₋₆)alkylsulphoximinyl,[(C₁₋₆)alkyl][N—(C₁₋₆)alkyl]sulphoximinyl, (C₁₋₆)alkylsulphonylaminocarbonyl, (C₂₋₆)alkylcarbonylaminosulphonyl, (C₁₋₆)alkoxyaminocarbonyl,tetrazolyl or hydroxyoxadiazolyl.

Typical values of R³² include hydrogen, fluoro, cyano, hydroxy,hydroxymethyl, methylsulphonyl, formyl, carboxy, carboxymethyl,carboxyethyl, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl,methoxycarbonylmethyl, methoxycarbonylethyl, ethoxycarbonylmethyl,ethoxycarbonylethyl, aminosulphonyl, methylsulphoximinyl,(methyl)(N-methyl)sulphoximinyl, methylsulphonylaminocarbonyl,acetylaminosulphonyl, methoxyaminocarbonyl, tetrazolyl andhydroxyoxadiazolyl.

In a particular embodiment, R³² represents hydroxy.

In a selected embodiment, R³² represents carboxy.

Generally, R³³ represents hydrogen, halogen or C₁₋₆ alkyl.

Suitably, R³³ represents hydrogen or C₁₋₆ alkyl.

Selected values of R³³ include hydrogen, fluoro, methyl, ethyl,isopropyl, trifluoromethyl, hydroxy, hydroxymethyl, methoxy, amino andcarboxy.

Selected values of R³³ include hydrogen and methyl.

In a first embodiment, R³³ represents hydrogen. In a second embodiment,R³³ represents halogen. In one aspect of that embodiment, R³³ representsfluoro. In a third embodiment, R³³ represents C₁₋₆ alkyl. In a firstaspect of that embodiment, R³³ represents methyl. In a second aspect ofthat embodiment, R³³ represents ethyl. In a third aspect of thatembodiment, R³³ represents isopropyl. In a fourth embodiment, R³³represents trifluoromethyl. In a fifth embodiment, R³³ representshydroxy. In a sixth embodiment, R³³ represents hydroxy(C₁₋₆)alkyl. Inone aspect of that embodiment, R³³ represents hydroxymethyl. In aseventh embodiment, R³³ represents C₁₋₆ alkoxy. In one aspect of thatembodiment, R³³ represents methoxy. In an eighth embodiment, R³³represents amino. In a ninth embodiment, R³³ represents carboxy.

In a first embodiment, R³⁴ represents hydrogen. In a second embodiment,R³⁴ represents halogen. In one aspect of that embodiment, R³⁴ representsfluoro. In a third embodiment, R³⁴ represents halo(C₁₋₆)alkyl. In oneaspect of that embodiment, R³⁴ represents fluoromethyl. In a fourthembodiment, R³⁴ represents hydroxy. In a fifth embodiment, R³⁴represents C₁₋₆ alkoxy, especially methoxy. In a sixth embodiment, R³⁴represents C₁₋₆ alkylthio, especially methylthio. In a seventhembodiment, R³⁴ represents C₁₋₆ alkylsulphinyl, especiallymethylsulphinyl. In an eighth embodiment, R³⁴ represents C₁₋₆alkylsulphonyl, especially methylsulphonyl. In a ninth embodiment, R³⁴represents amino. In a tenth embodiment, R³⁴ represents C₁₋₆ alkylamino,especially methylamino. In an eleventh embodiment, R³⁴ representsdi(C₁₋₆)alkylamino, especially dimethylamino. In a twelfth embodiment,R³⁴ represents (C₂₋₆)alkylcarbonylamino, especially acetylamino. In athirteenth embodiment, R³⁴ represents(C₂₋₆)alkylcarbonylamino(C₁₋₆)alkyl, especially acetylaminomethyl. In afourteenth embodiment, R³⁴ represents (C₁₋₆)alkylsulphonylamino,especially methylsulphonylamino. In a fifteenth embodiment, R³⁴represents (C₁₋₆)alkylsulphonylamino(C₁₋₆)alkyl, especiallymethylsulphonylaminomethyl.

Typically, R³⁴ represents hydrogen, halogen, halo(C₁₋₆)alkyl, hydroxy or(C₂₋₆)alkylcarbonylamino(C₁₋₆)alkyl.

Selected values of R³⁴ include hydrogen, fluoro, fluoromethyl, hydroxy,methoxy, methylthio, methylsulphinyl, methylsulphonyl, amino,methylamino, dimethylamino and acetylaminomethyl.

Particular values of R³⁴ include hydrogen, fluoro, fluoromethyl, hydroxyand acetylaminomethyl.

Suitably, R³⁴ represents hydrogen or hydroxy.

An alternative sub-class of compounds according to the invention isrepresented by the compounds of formula (IIM) and N-oxides thereof, andpharmaceutically acceptable salts and solvates thereof, and glucuronidederivatives thereof, and co-crystals thereof:

wherein

E, Q, Z, W, R¹², R¹⁵, R¹⁶ and R²¹ are as defined above.

With specific reference to formula (IIM), the integer W is suitably O, Sor N—R³¹, especially S or N—R³¹.

Specific novel compounds in accordance with the present inventioninclude each of the compounds whose preparation is described in theaccompanying Examples, and pharmaceutically acceptable salts andsolvates thereof, and co-crystals thereof.

The compounds in accordance with the present invention are beneficial inthe treatment and/or prevention of various human ailments. These includeautoimmune and inflammatory disorders; neurological andneurodegenerative disorders; pain and nociceptive disorders;cardiovascular disorders; metabolic disorders; ocular disorders; andoncological disorders.

Inflammatory and autoimmune disorders include systemic autoimmunedisorders, autoimmune endocrine disorders and organ-specific autoimmunedisorders. Systemic autoimmune disorders include systemic lupuserythematosus (SLE), psoriasis, psoriatic arthropathy, vasculitis,polymyositis, scleroderma, multiple sclerosis, systemic sclerosis,ankylosing spondylitis, rheumatoid arthritis, non-specific inflammatoryarthritis, juvenile inflammatory arthritis, juvenile idiopathicarthritis (including oligoarticular and polyarticular forms thereof),anaemia of chronic disease (ACD), Still's disease (juvenile and/or adultonset), Behcet's disease and Sjogren's syndrome. Autoimmune endocrinedisorders include thyroiditis. Organ-specific autoimmune disordersinclude Addison's disease, haemolytic or pernicious anaemia, acutekidney injury (AKI; including cisplatin-induced AKI), diabeticnephropathy (DN), obstructive uropathy (including cisplatin-inducedobstructive uropathy), glomerulonephritis (including Goodpasture'ssyndrome, immune complex-mediated glomerulonephritis and antineutrophilcytoplasmic antibodies (ANCA)-associated glomerulonephritis), lupusnephritis (LN), minimal change disease, Graves' disease, idiopathicthrombocytopenic purpura, inflammatory bowel disease (including Crohn'sdisease, ulcerative colitis, indeterminate colitis and pouchitis),pemphigus, atopic dermatitis, autoimmune hepatitis, primary biliarycirrhosis, autoimmune pneumonitis, autoimmune carditis, myastheniagravis, spontaneous infertility, osteoporosis, osteopenia, erosive bonedisease, chondritis, cartilage degeneration and/or destruction,fibrosing disorders (including various forms of hepatic and pulmonaryfibrosis), asthma, rhinitis, chronic obstructive pulmonary disease(COPD), respiratory distress syndrome, sepsis, fever, muscular dystrophy(including Duchenne muscular dystrophy) and organ transplant rejection(including kidney allograft rejection).

Neurological and neurodegenerative disorders include Alzheimer'sdisease, Parkinson's disease, Huntington's disease, ischaemia, stroke,amyotrophic lateral sclerosis, spinal cord injury, head trauma, seizuresand epilepsy.

Cardiovascular disorders include thrombosis, cardiac hypertrophy,hypertension, irregular contractility of the heart (e.g. during heartfailure), and sexual disorders (including erectile dysfunction andfemale sexual dysfunction). Modulators of TNFα function may also be ofuse in the treatment and/or prevention of myocardial infarction (see J.J. Wu et al., JAMA, 2013, 309, 2043-2044).

Metabolic disorders include diabetes (including insulin-dependentdiabetes mellitus and juvenile diabetes), dyslipidemia and metabolicsyndrome.

Ocular disorders include retinopathy (including diabetic retinopathy,proliferative retinopathy, non-proliferative retinopathy and retinopathyof prematurity), macular oedema (including diabetic macular oedema),age-related macular degeneration (ARMD), vascularisation (includingcorneal vascularisation and neovascularisation), retinal vein occlusion,and various forms of uveitis and keratitis.

Oncological disorders, which may be acute or chronic, includeproliferative disorders, especially cancer, and cancer-associatedcomplications (including skeletal complications, cachexia and anaemia).Particular categories of cancer include haematological malignancy(including leukaemia and lymphoma) and non-haematological malignancy(including solid tumour cancer, sarcoma, meningioma, glioblastomamultiforme, neuroblastoma, melanoma, gastric carcinoma and renal cellcarcinoma). Chronic leukaemia may be myeloid or lymphoid. Varieties ofleukaemia include lymphoblastic T cell leukaemia, chronic myelogenousleukaemia (CML), chronic lymphocytic/lymphoid leukaemia (CLL),hairy-cell leukaemia, acute lymphoblastic leukaemia (ALL), acutemyelogenous leukaemia (AML), myelodysplastic syndrome, chronicneutrophilic leukaemia, acute lymphoblastic T cell leukaemia,plasmacytoma, immunoblastic large cell leukaemia, mantle cell leukaemia,multiple myeloma, acute megakaryoblastic leukaemia, acute megakaryocyticleukaemia, promyelocytic leukaemia and erythroleukaemia. Varieties oflymphoma include malignant lymphoma, Hodgkin's lymphoma, non-Hodgkin'slymphoma, lymphoblastic T cell lymphoma, Burkitt's lymphoma, follicularlymphoma, MALT 1 lymphoma and marginal zone lymphoma. Varieties ofnon-haematological malignancy include cancer of the prostate, lung,breast, rectum, colon, lymph node, bladder, kidney, pancreas, liver,ovary, uterus, cervix, brain, skin, bone, stomach and muscle. Modulatorsof TNFα function may also be used to increase the safety of the potentanticancer effect of TNF (see F. V. Hauwermeiren et al., J. Clin.Invest., 2013, 123, 2590-2603).

The present invention also provides a pharmaceutical composition whichcomprises a compound in accordance with the invention as describedabove, or a pharmaceutically acceptable salt or solvate thereof, inassociation with one or more pharmaceutically acceptable carriers.

Pharmaceutical compositions according to the invention may take a formsuitable for oral, buccal, parenteral, nasal, topical, ophthalmic orrectal administration, or a form suitable for administration byinhalation or insufflation.

For oral administration, the pharmaceutical compositions may take theform of, for example, tablets, lozenges or capsules prepared byconventional means with pharmaceutically acceptable excipients such asbinding agents (e.g. pregelatinised maize starch, polyvinylpyrrolidoneor hydroxypropyl methyl cellulose); fillers (e.g. lactose,microcrystalline cellulose or calcium hydrogenphosphate); lubricants(e.g. magnesium stearate, talc or silica); disintegrants (e.g. potatostarch or sodium glycollate); or wetting agents (e.g. sodium laurylsulphate). The tablets may be coated by methods well known in the art.Liquid preparations for oral administration may take the form of, forexample, solutions, syrups or suspensions, or they may be presented as adry product for constitution with water or other suitable vehicle beforeuse. Such liquid preparations may be prepared by conventional means withpharmaceutically acceptable additives such as suspending agents,emulsifying agents, non-aqueous vehicles or preservatives. Thepreparations may also contain buffer salts, flavouring agents, colouringagents or sweetening agents, as appropriate.

Preparations for oral administration may be suitably formulated to givecontrolled release of the active compound.

For buccal administration, the compositions may take the form of tabletsor lozenges formulated in conventional manner.

The compounds of formula (I) may be formulated for parenteraladministration by injection, e.g. by bolus injection or infusion.Formulations for injection may be presented in unit dosage form, e.g. inglass ampoules or multi-dose containers, e.g. glass vials. Thecompositions for injection may take such forms as suspensions, solutionsor emulsions in oily or aqueous vehicles, and may contain formulatoryagents such as suspending, stabilising, preserving and/or dispersingagents. Alternatively, the active ingredient may be in powder form forconstitution with a suitable vehicle, e.g. sterile pyrogen-free water,before use.

In addition to the formulations described above, the compounds offormula (I) may also be formulated as a depot preparation. Suchlong-acting formulations may be administered by implantation or byintramuscular injection.

For nasal administration or administration by inhalation, the compoundsaccording to the present invention may be conveniently delivered in theform of an aerosol spray presentation for pressurised packs or anebuliser, with the use of a suitable propellant, e.g.dichlorodifluoromethane, fluorotrichloromethane,dichlorotetrafluoroethane, carbon dioxide or other suitable gas ormixture of gases.

The compositions may, if desired, be presented in a pack or dispenserdevice which may contain one or more unit dosage forms containing theactive ingredient. The pack or dispensing device may be accompanied byinstructions for administration.

For topical administration the compounds of use in the present inventionmay be conveniently formulated in a suitable ointment containing theactive component suspended or dissolved in one or more pharmaceuticallyacceptable carriers. Particular carriers include, for example, mineraloil, liquid petroleum, propylene glycol, polyoxyethylene,polyoxypropylene, emulsifying wax and water. Alternatively, thecompounds of use in the present invention may be formulated in asuitable lotion containing the active component suspended or dissolvedin one or more pharmaceutically acceptable carriers. Particular carriersinclude, for example, mineral oil, sorbitan monostearate, polysorbate60, cetyl esters wax, cetearyl alcohol, benzyl alcohol, 2-octyldodecanoland water.

For ophthalmic administration the compounds of use in the presentinvention may be conveniently formulated as micronized suspensions inisotonic, pH-adjusted sterile saline, either with or without apreservative such as a bactericidal or fungicidal agent, for examplephenylmercuric nitrate, benzylalkonium chloride or chlorhexidineacetate. Alternatively, for ophthalmic administration compounds may beformulated in an ointment such as petrolatum.

For rectal administration the compounds of use in the present inventionmay be conveniently formulated as suppositories. These can be preparedby mixing the active component with a suitable non-irritating excipientwhich is solid at room temperature but liquid at rectal temperature andso will melt in the rectum to release the active component. Suchmaterials include, for example, cocoa butter, beeswax and polyethyleneglycols.

The quantity of a compound of use in the invention required for theprophylaxis or treatment of a particular condition will vary dependingon the compound chosen and the condition of the patient to be treated.In general, however, daily dosages may range from around 10 ng/kg to1000 mg/kg, typically from 100 ng/kg to 100 mg/kg, e.g. around 0.01mg/kg to 40 mg/kg body weight, for oral or buccal administration, fromaround 10 ng/kg to 50 mg/kg body weight for parenteral administration,and from around 0.05 mg to around 1000 mg, e.g. from around 0.5 mg toaround 1000 mg, for nasal administration or administration by inhalationor insufflation.

If desired, a compound in accordance with the present invention may beco-administered with another pharmaceutically active agent, e.g. ananti-inflammatory molecule such as methotrexate or prednisolone.

The compounds of formula (I) above may be prepared by a process whichcomprises reacting a compound of formula Z-Q-CO₂H or a carboxylate saltthereof (e.g. a carboxylate salt with an alkali metal such as lithium,sodium or potassium) with a compound of formula (III):

wherein E, Q, Y, Z, R¹, R² and R³ are as defined above.

The reaction may advantageously be performed in the presence of apeptide coupling reagent such as1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]-pyridinium3-oxid hexafluorophosphate (HATU), optionally in the presence of asuitable base, e.g. an organic base such as N,N-diisopropylethylamine ortriethylamine. The reaction is conveniently effected at ambient orelevated temperature in a suitable solvent, e.g. a dipolar aproticsolvent such as N,N-dimethylformamide, and/or a chlorinated solvent suchas dichloromethane.

Alternatively, the reaction may be accomplished in the presence of acoupling reagent such as 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (EDCI), typically in the presence of a reagent such as1-hydroxybenzotriazole (HOBT) and a suitable base, e.g. an organic basesuch as N,N-diisopropylethylamine or triethylamine. The reaction isconveniently effected at ambient temperature in a suitable solvent, e.g.a dipolar aprotic solvent such as N,N-dimethylformamide, or achlorinated solvent such as dichloromethane.

The product thereby obtained is suitably treated with an acid, ideallyan organic acid such as acetic acid, or p-toluenesulphonic acid, or amineral acid such as hydrochloric acid, typically at an elevatedtemperature.

Alternatively, the reaction may conveniently be effected at an elevatedtemperature in the presence of a mineral acid, e.g. hydrochloric acid.

Alternatively, the reaction may conveniently be effected at an elevatedtemperature in the presence of a lower alkanol, e.g. a C₁₋₄ alkanol suchas methanol.

In an alternative procedure, the compounds of formula (I) above whereinE represents a covalent bond or an optionally substituted straight orbranched C₁₋₄ alkylene chain may be prepared by a process whichcomprises reacting a compound of formula L¹-E¹-Y with a compound offormula (IV):

wherein Q, Y, Z, R¹, R² and R³ are as defined above, E¹ represents acovalent bond or an optionally substituted straight or branched C₁₋₄alkylene chain, and L¹ represents a suitable leaving group.

The leaving group L¹ is typically a halogen atom, e.g. chloro or bromo.

The reaction is conveniently effected at ambient or elevated temperaturein a suitable solvent, e.g. a dipolar aprotic solvent such asN,N-dimethylformamide, or a chlorinated solvent such as dichloromethane,or a cyclic ether such as tetrahydrofuran, or an organic nitrile such asacetonitrile, or an organic sulfoxide such as dimethylsulfoxide. Thereaction may be performed in the presence of a suitable base, e.g. aninorganic base such as potassium carbonate, cesium carbonate or sodiumhydride.

The intermediates of formula (IV) above may be prepared by reacting acompound of formula Z-Q-CO₂H or a carboxylate salt thereof (e.g. acarboxylate salt with an alkali metal such as lithium, sodium orpotassium) with a compound of formula (V):

wherein Q, Z, R¹, R² and R³ are as defined above; under conditionsanalogous to those described above for the reaction between compound(III) and a compound of formula Z-Q-CO₂H or a carboxylate salt thereof.

The intermediates of formula (III) above may be prepared by reducing acompound of formula (VI):

wherein E, Y, R¹, R² and R³ are as defined above.

The transformation is conveniently effected by catalytic hydrogenationof compound (VI), which typically comprises treating compound (VI) withgaseous hydrogen in the presence of a hydrogenation catalyst such aspalladium on carbon, or platinum on carbon.

Alternatively, the reduction of compound (VI) may be effected bytreatment with elemental iron or zinc, typically at an elevatedtemperature in the presence of ammonium chloride.

Alternatively, the reduction of compound (VI) may be effected bytreatment with tin(II) chloride, typically at an elevated temperature inthe presence of a mineral acid such as hydrochloric acid.

The intermediates of formula (VI) wherein E represents a covalent bondor an optionally substituted straight or branched C₁₋₄ alkylene chainmay be prepared by reacting a compound of formula L¹-E¹-Y with acompound of formula (VII):

wherein E¹, Y, R¹, R², R³ and L¹ are as defined above; under conditionsanalogous to those described above for the reaction between compound(IV) and a compound of formula L¹-E¹-Y.

Alternatively, the intermediates of formula (VI) wherein E represents acovalent bond or an optionally substituted straight or branched C₁₋₄alkylene chain may be prepared by reacting a compound of formulaY-E¹-NH₂ with a compound of formula (VIII):

wherein E¹, Y, R¹, R² and R³ are as defined above.

The reaction is conveniently effected at ambient or elevated temperaturein a suitable solvent, e.g. 1-methyl-2-pyrrolidinone (NMP), ahydrocarbon solvent such as toluene, a cyclic ether such astetrahydrofuran, a dipolar aprotic solvent such asN,N-dimethylformamide, or an organic nitrile such as acetonitrile. Thereaction may be performed in the presence of a suitable base, e.g. aninorganic base such as sodium hydride or potassium carbonate.

In another procedure, the compounds of formula (I) above, wherein Qcorresponds to a group of formula —CH(OH)-Q¹-, may be prepared by aprocess which comprises reacting an aldehyde of formula OHC-Q¹-Z with acompound of formula (IX):

wherein E, Y, Z, R¹, R² and R³ are as defined above.

The reaction is conveniently effected in the presence of a strong base,e.g. n-butyllithium or lithium diisopropylamide (LDA). The reaction iscarried out in a suitable solvent, e.g. a cyclic ether such astetrahydrofuran.

The intermediates of formula (IX) above wherein E represents a covalentbond or an optionally substituted straight or branched C₁₋₄ alkylenechain may be prepared by reacting a compound of formula L¹-E¹-Y with acompound of formula (X):

wherein E¹, Y, R¹, R², R³ and L¹ are as defined above; under conditionsanalogous to those described above for the reaction between compound(IV) and a compound of formula L¹-E¹-Y.

Alternatively, the intermediates of formula (IX) above may be preparedby reacting a compound of formula (III) as defined above with formicacid, ideally at ambient temperature.

The intermediates of formula (IX) above wherein E represents —N(H)— maybe prepared by reacting a compound of formula L²-Y with a compound offormula (XI):

wherein Y, R¹, R² and R³ are as defined above, and L² represents asuitable leaving group; in the presence of a transition metal catalyst.

The leaving group L² is typically a halogen atom, e.g. bromo.

A suitable transition metal catalyst for use in the above reaction istris(dibenzylideneacetone)dipalladium(0), in which case the reaction isconveniently performed in the presence of2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl. The reaction issuitably carried out at an elevated temperature in a suitable solvent,e.g. N,N-dimethylformamide, typically in the presence of a base, e.g. aninorganic base such as cesium carbonate.

In a further procedure, the compounds of formula (I) above wherein Zrepresents a 1H-[1,2,3]triazol-1-yl moiety, optionally substituted inthe 4-position, may be prepared by a process which comprises reacting acompound of formula H—C≡C—R^(z) with a compound of formula (XII):

wherein E, Q, Y, R¹, R² and R³ are as defined above, and R^(z)represents an optional substituent on Z.

The reaction is conveniently performed in the presence of copper sulfatepentahydrate and sodium ascorbate. Suitably, the reaction is carried outat ambient temperature in a suitable solvent, e.g. a cyclic ethersolvent such as tetrahydrofuran, typically in admixture with water.

The intermediates of formula (XII) above wherein E represents a covalentbond or an optionally substituted straight or branched C₁₋₄ alkylenechain may be prepared by reacting a compound of formula (XIII):

wherein Q, R¹, R² and R³ are as defined above, and L³ represents asuitable leaving group; with sodium azide; followed by reaction of theresulting compound with a compound of formula L¹-E¹-Y under conditionsanalogous to those described above for the reaction between compound(IV) and a compound of formula L¹-E¹-Y.

The leaving group L³ is typically a halogen atom, e.g. chloro.

The reaction between compound (XIII) and sodium azide is convenientlyeffected at ambient temperature in a suitable solvent, e.g.N,N-dimethylformamide.

The compounds of formula (I) above wherein Q represents —S— may beprepared by a process which comprises reacting a compound of formulaZ—S—Z with a compound of formula (IX) as defined above.

The reaction is conveniently effected at ambient temperature in asuitable solvent, e.g. N,N-dimethylformamide. The reaction may beperformed in the presence of a suitable base, e.g. an inorganic basesuch as potassium carbonate.

In a further procedure, the compounds of formula (I) above may beprepared by a process which comprises cyclising a compound of formula(XIV):

wherein E, Q, Y, Z, R¹, R² and R³ are as defined above.

The cyclisation reaction is conveniently effected by heating compound(XIV) in acetic acid.

The intermediates of formula (XIV) above may be prepared by a processwhich comprises reacting an aldehyde derivative of formula Y-E²-CHO witha compound of formula (XV):

wherein Q, Y, Z, R¹, R² and R³ are as defined above, and -E²-CH₂—corresponds to a group E as defined above; in the presence of a reducingagent.

The reducing agent for use in the above reaction is suitably sodiumtriacetoxyborohydride or sodium borohydride.

In a further procedure, the compounds of formula (I) above wherein -Q-Zrepresents dimethylamino may be prepared by a process which comprisesreacting a compound of formula (III) as defined above with(dichloromethylene)dimethylammonium chloride.

The reaction is conveniently effected in a suitable solvent, e.g. achlorinated solvent such as dichloromethane, typically in the presenceof a base, e.g. an organic base such as N,N-diisopropylethylamine.

In a further procedure, the compounds of formula (I) above may beprepared by a process which comprises cyclising a compound of formula(XVI):

wherein E, Q, Y, Z, R¹, R² and R³ are as defined above.

The cyclisation reaction is conveniently effected by heating compound(XVI) in acetic anhydride, then acetic acid.

The intermediates of formula (XVI) above may be prepared by reducing acompound of formula (XVII):

wherein E, Q, Y, Z, R¹, R² and R³ are as defined above; under conditionsanalogous to those described above for the reduction of compound (VI).

The intermediates of formula (XVII) wherein E represents a covalent bondor an optionally substituted straight or branched C₁₋₄ alkylene chainmay be prepared by reacting a compound of formula L¹-E¹-Y with acompound of formula (XVIII):

wherein E¹, Q, Y, Z, R¹, R², R³ and L¹ are as defined above; underconditions analogous to those described above for the reaction betweencompound (IV) and a compound of formula L¹-E¹-Y.

The intermediates of formula (XVIII) above may be prepared by heating acompound of formula (VII) as defined above with an anhydride of formula(Z-Q-CO)₂O, suitably in the presence of acetic acid and a mineral acidsuch as sulphuric acid.

As will be appreciated, the compounds of formula (IX) above correspondto compounds of formula (I) wherein Q represents a covalent bond and Zis hydrogen.

Where they are not commercially available, the starting materials offormula (V), (VII), (VIII), (X), (XI), (XIII) and (XV) may be preparedby methods analogous to those described in the accompanying Examples, orby standard methods well known from the art.

It will be understood that any compound of formula (I) initiallyobtained from any of the above processes may, where appropriate,subsequently be elaborated into a further compound of formula (I) bytechniques known from the art. By way of example, a compound of formula(I) wherein E represents —CH₂— may be converted into the correspondingcompound wherein E represents —CH(CH₃)— by treatment with a methylhalide, e.g. methyl iodide, in the presence of a base such as lithiumhexamethyldisilazide.

A compound of formula (I) which contains a hydroxy group may bealkylated by treatment with the appropriate alkyl halide in the presenceof a base, e.g. sodium hydride, or silver oxide. A compound of formula(I) wherein -Q-Z represents —CH₂OH may be arylated in a two-stepprocedure which comprises: (i) treatment with thionyl chloride; and (ii)treatment of the chloro derivative thereby obtained with the appropriatearyl or heteroaryl hydroxide. A compound of formula (I) wherein -Q-Zrepresents —CH₂OH may be converted into the corresponding compound offormula (I) wherein -Q-Z represents —CH₂S—Z via a two-step procedurewhich comprises: (i) treatment with thionyl chloride; and (ii) treatmentof the chloro derivative thereby obtained with a compound of formulaZ—SH, typically in the presence of a base, e.g. an inorganic base suchas potassium carbonate. A compound of formula (I) wherein -Q-Zrepresents —CH₂OH may be converted into the corresponding compound offormula (I) wherein -Q-Z represents —CH₂CN via a two-step procedurewhich comprises: (i) treatment with thionyl chloride; and (ii) treatmentof the chloro derivative thereby obtained with a cyanide salt such assodium cyanide. A compound of formula (I) which contains hydroxy may beconverted into the corresponding fluoro-substituted compound bytreatment with diethylaminosulfur trifluoride (DAST) orbis(2-methoxyethyl)aminosulfur trifluoride (BAST). A compound of formula(I) which contains hydroxy may be converted into the correspondingdifluoro-substituted compound via a two-step procedure which comprises:(i) treatment with an oxidising agent, e.g. manganese dioxide; and (ii)treatment of the carbonyl-containing compound thereby obtained withDAST.

A compound of formula (I) wherein -Q-Z represents —CH₂OH may beconverted into the corresponding compound wherein -Q-Z represents—CH(OH)Z in a two-step procedure which comprises: (i) oxidation with asuitable oxidising agent, e.g. Dess-Martin periodinane or manganese(IV)oxide; and (ii) treatment of the aldehyde derivative thereby obtainedwith a Grignard reagent, e.g. a compound of formula Z—MgBr or Z—MgCl.

A compound of formula (I) wherein -Q-Z represents —CH₂OH may beconverted into the corresponding compound wherein -Q-Z represents—CH(OH)CF₃ in a two-step procedure which comprises: (i) oxidation with asuitable oxidising agent, e.g. Dess-Martin periodinane or manganese(IV)oxide; and (ii) treatment of the aldehyde derivative thereby obtainedwith (trifluoromethyl)trimethylsilane and cesium fluoride.

A compound of formula (I) which contains an N—H moiety may be alkylatedby treatment with the appropriate alkyl halide, typically at an elevatedtemperature in an organic solvent such as acetonitrile; or at ambienttemperature in the presence of a base, e.g. an alkali metal carbonatesuch as potassium carbonate or cesium carbonate, in a suitable solvent,e.g. a dipolar aprotic solvent such as N,N-dimethylformamide.Alternatively, a compound of formula (I) which contains an N—H moietymay be alkylated by treatment with the appropriate alkyl tosylate in thepresence of a base, e.g. an inorganic base such as sodium hydride, or anorganic base such as 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU).

A compound of formula (I) which contains an N—H moiety may be methylatedby treatment with formaldehyde in the presence of a reducing agent, e.g.sodium triacetoxyborohydride.

A compound of formula (I) which contains an N—H moiety may be acylatedby treatment with the appropriate acid chloride, e.g. acetyl chloride,or with the appropriate carboxylic acid anhydride, e.g. aceticanhydride, typically at ambient temperature in the presence of a base,e.g. an organic base such as triethylamine.

A compound of formula (I) which contains an N—H moiety may be convertedinto the corresponding compound wherein the nitrogen atom is substitutedby C₁₋₆ alkylsulphonyl, e.g. methylsulphonyl, by treatment with theappropriate C₁₋₆ alkylsulphonyl chloride, e.g. methanesulphonylchloride, or with the appropriate C₁₋₆ alkylsulphonic acid anhydride,e.g. methanesulphonic anhydride, typically at ambient temperature in thepresence of a base, e.g. an organic base such as triethylamine orN,N-diisopropylethylamine.

A compound of formula (I) substituted by amino (—NH₂) may be convertedinto the corresponding compound substituted by C₁₋₆ alkylsulphonylamino,e.g. methylsulphonylamino, or bis[(C₁₋₆)alkylsulphonyl]amino, e.g.bis(methylsulphonyl)amino, by treatment with the appropriate C₁₋₆alkylsulphonyl halide, e.g. a C₁₋₆ alkylsulphonyl chloride such asmethanesulphonyl chloride. Similarly, a compound of formula (I)substituted by hydroxy (—OH) may be converted into the correspondingcompound substituted by C₁₋₆ alkylsulphonyloxy, e.g. methylsulphonyloxy,by treatment with the appropriate C₁₋₆ alkylsulphonyl halide, e.g. aC₁₋₆ alkylsulphonyl chloride such as methanesulphonyl chloride.

A compound of formula (I) containing the moiety —S— may be convertedinto the corresponding compound containing the moiety —S(O)— bytreatment with 3-chloroperoxybenzoic acid. Likewise, a compound offormula (I) containing the moiety —S(O)— may be converted into thecorresponding compound containing the moiety —S(O)₂— by treatment with3-chloroperoxybenzoic acid. Alternatively, a compound of formula (I)containing the moiety —S— may be converted into the correspondingcompound containing the moiety —S(O)₂— by treatment with Oxone®(potassium peroxymonosulfate).

A compound of formula (I) containing an aromatic nitrogen atom may beconverted into the corresponding N-oxide derivative by treatment with3-chloroperoxybenzoic acid.

A bromophenyl derivative of formula (I) may be converted into thecorresponding optionally substituted 2-oxopyrrolidin-1-ylphenyl or2-oxooxazolidin-3-ylphenyl derivative by treatment with pyrrolidin-2-oneor oxazolidin-2-one, or an appropriately substituted analogue thereof.The reaction is conveniently effected at an elevated temperature in thepresence of copper(I) iodide, trans-NX-dimethylcyclohexane-1,2-diamineand an inorganic base such as potassium carbonate.

A compound of formula (I) wherein R¹ represents halogen, e.g. bromo orchloro, may be converted into the corresponding compound wherein R¹represents an optionally substituted aryl or heteroaryl moiety bytreatment with the appropriately substituted aryl or heteroaryl boronicacid or a cyclic ester thereof formed with an organic diol, e.g.pinacol, 1,3-propanediol or neopentyl glycol. The reaction is typicallyeffected in the presence of a transition metal catalyst, e.g.[1,1¹-bis(diphenylphosphino)ferrocene]dichloropalladium(II),dichloro[1,1¹-bis(di-tert-butylphosphino)ferrocene]palladium(II),tetrakis(triphenylphosphine)palladium(0),bis[3-(diphenylphosphanyl)cyclopenta-2,4-dien-1-yl]iron-dichloropalladium-dichloromethanecomplex, or tris(dibenzylideneacetone)dipalladium(0), and a base, e.g.an inorganic base such as sodium carbonate, potassium carbonate orcesium carbonate, or potassium phosphate.

A compound of formula (I) wherein R¹ represents halogen, e.g. bromo, maybe converted into the corresponding compound wherein R¹ represents anoptionally substituted aryl, heteroaryl or heterocycloalkenyl moiety viaa two-step procedure which comprises: (i) reaction withbis(pinacolato)diboron or bis(neopentyl glycolato)diboron; and (ii)reaction of the compound thereby obtained with an appropriatelyfunctionalised halo- or tosyloxy-substituted aryl, heteroaryl orheterocycloalkenyl derivative. Step (i) is conveniently effected in thepresence of a transition metal catalyst such as[1,1′-bis-(diphenylphosphino)ferrocene]dichloropalladium(II), orbis[3-(diphenylphosphanyl)-cyclopenta-2,4-dien-1-yl]iron-dichloropalladium-dichloromethanecomplex. Step (ii) is conveniently effected in the presence of atransition metal catalyst such astetrakis-(triphenylphosphine)palladium(0), orbis[3-(diphenylphosphanyl)cyclopenta-2,4-dien-1-yl]iron-dichloropalladium-dichloromethanecomplex, and a base, e.g. an inorganic base such as sodium carbonate orpotassium carbonate.

A compound of formula (I) wherein R¹ represents halogen, e.g. bromo, maybe converted into the corresponding compound wherein R¹ represents anoptionally substituted C₂₋₆ alkynyl moiety by treatment with anappropriately substituted alkyne derivative, e.g. 2-hydroxybut-3-yne.The reaction is conveniently accomplished with the assistance of atransition metal catalyst, e.g.tetrakis(triphenylphosphine)palladium(0), typically in the presence ofcopper(I) iodide and a base, e.g. an organic base such as triethylamine.

A compound of formula (I) wherein R¹ represents halogen, e.g. bromo, maybe converted into the corresponding compound wherein R¹ represents anoptionally substituted imidazol-1-yl moiety by treatment with theappropriately substituted imidazole derivative, typically in thepresence of copper(II) acetate and an organic base such asN,N,N′,N′-tetramethylethylenediamine (TMEDA).

A compound of formula (I) wherein R¹ represents halogen, e.g. bromo, maybe converted into the corresponding compound wherein R¹ represents2-(methoxycarbonyl)-ethyl via a two-step procedure which comprises: (i)reaction with methyl acrylate; and (ii) catalytic hydrogenation of thealkenyl derivative thereby obtained, typically by treatment with ahydrogenation catalyst, e.g. palladium on charcoal, under an atmosphereof hydrogen gas. Step (i) is typically effected in the presence of atransition metal catalyst, e.g. palladium(II) acetate orbis(dibenzylideneacetone)palladium(0), and a reagent such astri(ortho-tolyl)phosphine.

In general, a compound of formula (I) containing a —C═C— functionalitymay be converted into the corresponding compound containing a —CH—CH—functionality by catalytic hydrogenation, typically by treatment with ahydrogenation catalyst, e.g. palladium on charcoal, under an atmosphereof hydrogen gas, optionally in the presence of a base, e.g. an alkalimetal hydroxide such as sodium hydroxide.

A compound of formula (I) wherein R¹ represents 6-methoxypyridin-3-ylmay be converted into the corresponding compound wherein R¹ represents2-oxo-1,2-dihydropyridin-5-yl by treatment with pyridine hydrochloride;or by heating with a mineral acid such as hydrochloric acid. Byutilising similar methodology, a compound of formula (I) wherein R¹represents 6-methoxy-4-methylpyridin-3-yl may be converted into thecorresponding compound wherein R¹ represents4-methyl-2-oxo-1,2-dihydropyridin-5-yl; and a compound of formula (I)wherein R¹ represents 6-methoxy-5-methylpyridin-3-yl may be convertedinto the corresponding compound wherein R¹ represents3-methyl-2-oxo-1,2-dihydropyridin-5-yl.

A compound of formula (I) wherein R¹ represents2-oxo-1,2-dihydropyridin-5-yl may be converted into the correspondingcompound wherein R¹ represents 2-oxopiperidin-5-yl by catalytichydrogenation, typically by treatment with gaseous hydrogen in thepresence of a hydrogenation catalyst such as platinum(IV) oxide.

A compound of formula (I) containing an ester moiety, e.g. a C₂₋₆alkoxycarbonyl group such as methoxycarbonyl or ethoxycarbonyl, may beconverted into the corresponding compound containing a carboxy (—CO₂H)moiety by treatment with an acid, e.g. a mineral acid such ashydrochloric acid.

A compound of formula (I) containing an N-(tert-butoxycarbonyl) moietymay be converted into the corresponding compound containing an N—Hmoiety by treatment with an acid, e.g. a mineral acid such ashydrochloric acid, or an organic acid such as trifluoroacetic acid.

A compound of formula (I) containing an ester moiety, e.g. a C₂₋₆alkoxycarbonyl group such as methoxycarbonyl or ethoxycarbonyl, mayalternatively be converted into the corresponding compound containing acarboxy (—CO₂H) moiety by treatment with a base, e.g. an alkali metalhydroxide selected from lithium hydroxide, sodium hydroxide andpotassium hydroxide; or an organic base such as sodium methoxide orsodium ethoxide.

A compound of formula (I) containing a carboxy (—CO₂H) moiety may beconverted into the corresponding compound containing an amide moiety bytreatment with the appropriate amine in the presence of a condensingagent such as 1-ethyl-3-(3-dimethyl-aminopropyl)carbodiimide.

A compound of formula (I) containing a carbonyl (C═O) moiety may beconverted into the corresponding compound containing a —C(CH₃)(OH)—moiety by treatment with methylmagnesium bromide. Similarly, a compoundof formula (I) containing a carbonyl (C═O) moiety may be converted intothe corresponding compound containing a —C(CF₃)(OH)— moiety by treatmentwith (trifluoromethyl)trimethylsilane and cesium fluoride. A compound offormula (I) containing a carbonyl (C═O) moiety may be converted into thecorresponding compound containing a —C(CH₂NO₂)(OH)— moiety by treatmentwith nitromethane.

A compound of formula (I) containing a hydroxymethyl moiety may beconverted into the corresponding compound containing a formyl (—CHO)moiety by treatment with an oxidising agent such as Dess-Martinperiodinane. A compound of formula (I) containing a hydroxymethyl moietymay be converted into the corresponding compound containing a carboxymoiety by treatment with an oxidising agent such as tetrapropylammoniumperruthenate.

A compound of formula (I) wherein R¹ represents a substituent containingat least one nitrogen atom, which substituent is linked to the remainderof the molecule via a nitrogen atom, may be prepared by reacting acompound of formula (I) wherein R¹ represents halogen, e.g. bromo, withthe appropriate compound of formula R¹—H [e.g.1-(pyridin-3-yl)piperazine or morpholine]. The reaction is convenientlyeffected with the assistance of a transition metal catalyst, e.g.tris(dibenzylideneacetone)dipalladium(0), in the presence of anamination ligand such as2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (XPhos) or2,2′-bis(diphenylphosphino)-1,1′-binaphthalene (BINAP) and a base, e.g.an inorganic base such as sodium tert-butoxide. Alternatively, thereaction may be effected using palladium diacetate, in the presence of areagent such as[2′,6′-bis(propan-2-yloxy)biphenyl-2-yl](dicyclohexyl)phosphane and abase, e.g. an inorganic base such as cesium carbonate.

A compound of formula (I) containing an oxo moiety can be converted intothe corresponding compound containing an ethoxycarbonylmethylidenemoiety by treatment with triethyl phosphonoacetate in the presence of abase such as sodium hydride.

A compound of formula (IIB) wherein R²¹ represents ethenyl may beprepared by reacting a compound of formula (IIB) wherein R²¹ representshalogen, e.g. chloro, with potassium vinyl trifluoroborate. The reactionis typically effected in the presence of a transition metal catalyst,e.g. [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), and abase, e.g. an organic base such as triethylamine.

A compound of formula (IIB) wherein R²¹ represents halogen, e.g. chloro,may be converted into the corresponding compound wherein R²¹ representsan optionally substituted C₄₋₇ cycloalkenyl moiety by treatment with theappropriately substituted cycloalkenyl boronic acid or a cyclic esterthereof formed with an organic diol, e.g. pinacol, 1,3-propanediol orneopentyl glycol. The reaction is typically effected in the presence ofa transition metal catalyst, e.g.bis[3-(diphenylphosphanyl)cyclopenta-2,4-dien-1-yl]iron-dichloropalladium-dichloromethanecomplex, and a base, e.g. an inorganic base such as potassium carbonate.

A compound of formula (IIB) wherein R²¹ represents a substituentcontaining at least one nitrogen atom, which substituent is linked tothe remainder of the molecule via a nitrogen atom, may be prepared byreacting a compound of formula (IIB) wherein R²¹ represents halogen,e.g. chloro, with the appropriate compound of formula R²¹—H [e.g.2-methoxyethylamine, N-methyl-L-alanine, 2-aminocyclopentanecarboxylicacid, 3-aminocyclopentanecarboxylic acid,1-(aminomethyl)cyclopropanecarboxylic acid, methylazetidine-3-carboxylate, pyrrolidin-3-ol, pyrrolidine-3-carboxylic acid,piperidine-2-carboxylic acid, piperidine-3-carboxylic acid,4-(1H-tetrazol-5-yl)piperidine, piperazine,1-(methylsulfonyl)piperazine, piperazin-2-one,2-(piperazin-1-yl)propanoic acid, morpholine, morpholine-2-carboxylicacid, thiomorpholine, thiomorpholine 1,1-dioxide, 1,4-diazepan-5-one,2-oxa-5-azabicyclo[2.2.1]heptane or an appropriately substitutedazaspiroalkane], optionally in the presence of a base, e.g. an organicbase such as triethylamine or N,N-diisopropylethylamine and/or1-methyl-2-pyrrolidinone, or pyridine, or an inorganic base such aspotassium carbonate.

Where a mixture of products is obtained from any of the processesdescribed above for the preparation of compounds according to theinvention, the desired product can be separated therefrom at anappropriate stage by conventional methods such as preparative HPLC; orcolumn chromatography utilising, for example, silica and/or alumina inconjunction with an appropriate solvent system.

Where the above-described processes for the preparation of the compoundsaccording to the invention give rise to mixtures of stereoisomers, theseisomers may be separated by conventional techniques. In particular,where it is desired to obtain a particular enantiomer of a compound offormula (I) this may be produced from a corresponding mixture ofenantiomers using any suitable conventional procedure for resolvingenantiomers. Thus, for example, diastereomeric derivatives, e.g. salts,may be produced by reaction of a mixture of enantiomers of formula (I),e.g. a racemate, and an appropriate chiral compound, e.g. a chiral base.The diastereomers may then be separated by any convenient means, forexample by crystallisation, and the desired enantiomer recovered, e.g.by treatment with an acid in the instance where the diastereomer is asalt. In another resolution process a racemate of formula (I) may beseparated using chiral HPLC. Moreover, if desired, a particularenantiomer may be obtained by using an appropriate chiral intermediatein one of the processes described above. Alternatively, a particularenantiomer may be obtained by performing an enantiomer-specificenzymatic biotransformation, e.g. an ester hydrolysis using an esterase,and then purifying only the enantiomerically pure hydrolysed acid fromthe unreacted ester antipode. Chromatography, recrystallisation andother conventional separation procedures may also be used withintermediates or final products where it is desired to obtain aparticular geometric isomer of the invention.

During any of the above synthetic sequences it may be necessary and/ordesirable to protect sensitive or reactive groups on any of themolecules concerned. This may be achieved by means of conventionalprotecting groups, such as those described in Protective Groups inOrganic Chemistry, ed. J. F. W. McOmie, Plenum Press, 1973; and T. W.Greene & P. G. M. Wuts, Protective Groups in Organic Synthesis, JohnWiley & Sons, 3^(rd) edition, 1999. The protecting groups may be removedat any convenient subsequent stage utilising methods known from the art.

The following Examples illustrate the preparation of compounds accordingto the invention.

The compounds in accordance with this invention potently inhibit thebinding of a fluorescence conjugate to TNFα when tested in thefluorescence polarisation assay described below. Moreover, certaincompounds in accordance with this invention potently inhibitTNFα-induced NF-κB activation in the reporter gene assay describedbelow.

Fluorescence Polarisation Assay

Preparation of Compound (A)

1-(2,5-Dimethylbenzyl)-6-[4-(piperazin-1-ylmethyl)phenyl]-2-(pyridin-4-ylmethyl)-1H-benzimidazolehereinafter referred to as “Compound (A)” can be prepared by theprocedure described in Example 499 of WO 2013/186229 (published 19 Dec.2013); or by a procedure analogous thereto.

Preparation of Fluorescence Conjugate

Compound (A) (27.02 mg, 0.0538 mmol) was dissolved in DMSO (2 mL). 5(−6) Carboxy-fluorescein succinimyl ester (24.16 mg, 0.0510 mmol)(Invitrogen catalogue number: C1311) was dissolved in DMSO (1 mL) togive a bright yellow solution. The two solutions were mixed at roomtemperature, the mixture turning red in colour. The mixture was stirredat room temperature. Shortly after mixing a 20 μL aliquot was removedand diluted in a 80:20 mixture of AcOH:H₂O for LC-MS analysis on the1200RR-6140 LC-MS system. The chromatogram showed two closely elutingpeaks at retention times of 1.42 and 1.50 minutes, both with mass(M+H)⁺=860.8 amu, corresponding to the two products formed with the 5-and 6-substituted carboxyfluorescein group. A further peak at retentiontime 2.21 minutes had a mass of (M+H)⁺=502.8 amu, corresponding toCompound (A). No peak was observed for unreacted 5(−6)carboxyfluorescein succinimyl ester. The peak areas were 22.0%, 39.6%and 31.4% for the three signals, indicating a 61.6% conversion to thetwo isomers of the desired fluorescence conjugate at that time-point.Further 20 μL aliquots were extracted after several hours and then afterovernight stirring, diluted as before and subjected to LC-MS analysis.The percentage conversion was determined as 79.8% and 88.6% respectivelyat these time-points. The mixture was purified on a UV-directedpreparative HPLC system. The pooled purified fractions were freeze-driedto remove excess solvent. After freeze-drying, an orange solid (23.3 mg)was recovered, equivalent to 0.027 mmol of fluorescence conjugate,corresponding to an overall yield of 53% for the reaction andpreparative HPLC purification.

Inhibition of Binding of Fluorescence Conjugate to TNFα

Compounds were tested at 10 concentrations starting from 25 μM in afinal assay concentration of 5% DMSO, by pre-incubation with TNFα for 60minutes at ambient temperature in 20 mM Tris, 150 mM NaCl, 0.05% Tween20, before addition of the fluorescence conjugate and a furtherincubation for 20 hours at ambient temperature. The final concentrationsof TNFα and the fluorescence conjugate were 10 nM and 10 nM respectivelyin a total assay volume of 25 μL. Plates were read on a plate readercapable of detecting fluorescence polarisation (e.g. an Analyst HT platereader; or an Envision plate reader). An IC₅₀ value was calculated usingXLfit™ (4 parameter logistic model) in ActivityBase.

When tested in the fluorescence polarisation assay, the compounds of theaccompanying Examples were all found to exhibit IC₅₀ values of 50 μM orbetter.

Reporter Gene Assay

Inhibition of TNFα-induced NE-κB Activation

Stimulation of HEK-293 cells by TNFα leads to activation of the NF-κBpathway. The reporter cell line used to determine TNFα activity waspurchased from InvivoGen. HEK-Blue™ CD40L is a stable HEK-293transfected cell line expressing SEAP (secreted embryonic alkalinephosphatase) under the control of the IFNβ minimal promoter fused tofive NF-κB binding sites. Secretion of SEAP by these cells is stimulatedin a dose-dependent manner by TNFα, with an EC50 of 0.5 ng/mL for humanTNFα. Compounds were diluted from 10 mM DMSO stocks (final assayconcentration 0.3% DMSO) to generate a 10-point 3-fold serial dilutioncurve (e.g. 30,000 nM to 2 nM final concentration). Diluted compound waspreincubated with TNFα for 60 minutes prior to addition to a 384-wellmicrotitre plate and incubated for 18 h. The final TNFα concentration inthe assay plate was 0.5 ng/mL. SEAP activity was determined in thesupernatant using a colorimetric substrate, e.g. QUANTI-Blue™ orHEK-Blue™ Detection media (InvivoGen). Percentage inhibitions forcompound dilutions were calculated between a DMSO control and maximuminhibition (by excess control compound) and an IC₅₀ value calculatedusing XLfit™ (4 parameter logistic model) in ActivityBase.

When tested in the reporter gene assay, certain compounds of theaccompanying Examples were found to exhibit IC₅₀ values of 50 μM orbetter.

EXAMPLES

Abbreviations DCM: dichloromethane THF: tetrahydrofuran EtOH: ethanolEtOAc: ethyl acetate MeOH: methanol DMSO: dimethylsulfoxide DMF:N,N-dimethylformamide HOBT: 1-hydroxybenzotriazole DIPEA:N,N-diisopropylethylamine PTSA: p-toluenesulfonic acid TBAF:tetra-n-butylammonium fluoride LDA: lithium diisopropylamide HATU:1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5- b]pyridinium3-oxid hexafluorophosphate EDCI:1-(3-dimethylaminopropyl)-3-ethylcarbodiimide Pd(PPh₃)₄:tetrakis(triphenylphosphine)palladium(0) Pd-118:dichloro[1,1′-bis(di-tert-butylphosphino)ferrocene]palladium(II)Pd₂(dba)₃: tris(dibenzylideneacetone)dipalladium(0) SiO₂: silica h: hourM: mass HPLC: High Performance Liquid Chromatography LCMS: LiquidChromatography Mass Spectrometry ES+: Electrospray Positive IonisationRT: retention timeNomenclature

Compounds were named with the aid of ACD/Name Batch (Network) version11.01, and/or Accelrys Draw 4.0.

Analytical Conditions Analytical HPLC Method A Column: Waters AtlantisdC18 (2.1 × 100 mm, 3 μm column) Flow rate: 0.6 mL/minute Solvent A:0.1% formic acid/water Solvent B: 0.1% formic acid/acetonitrileInjection volume: 3 μL Column temperature: 40° C. UV detectionwavelength: 215 nm Eluent: 0.00-5.00 minutes, constant gradient from 95%solvent A + 5% solvent B to 100% solvent B; 5.00-5.40 minutes, 100%solvent B; 5.40-5.42 minutes, constant gradient from 100% solvent B to95% solvent A + 5% solvent B; 5.42-7.00 minutes, 95% solvent A + 5%solvent B. Method B Column: Waters Atlantis dC18 (2.1 × 50 mm, 3 μmcolumn) Flow rate: 1.0 mL/minute Solvent A: 0.1% formic acid/waterSolvent B: 0.1% formic acid/acetonitrile Injection volume: 3 μL UVdetection wavelength: 215 nm Eluent: 0.00-2.50 minutes, constantgradient from 95% solvent A + 5% solvent B to 100% solvent B; 2.50-2.70minutes, 100% solvent B; 2.71-3.00 minutes, 95% solvent A + 5% solventB. Method C Column: Phenomenex, Gemini C18 (2.0 mm × 100 mm, 3 μmcolumn) Flow rate: 0.5 mL/minute Solvent A: 2 nM ammoniumhydrogencarbonate in water Solvent B: acetonitrile Injection volume: 3μL Column temperature: 50° C. UV detection wavelength: 215 nm Eluent:0.00-5.50 minutes, constant gradient from 95% solvent A + 5% solvent Bto 100% solvent B; 5.50-5.90 minutes, 100% solvent B. MS detection usingWaters LCT or LCT Premier, or ZQ or ZMD. UV detection using Waters 2996photodiode array or Waters 2787 UV or Waters 2788 UV.

Intermediate 16-Chloro-N-[(2,5-dichlorophenyl)methyl]-3-nitropyridin-2-amine

To a solution of 2,6-dichloro-3-nitropyridine (5.0 g, 25.9 mmol) and2,5-dichloro-benzylamine (5.5 g, 4.2 mL) in toluene (20 mL) was addedsodium hydride (60% dispersion in mineral oil, 1.9 g, 33.7 mmol) at 0°C. The reaction mixture was warmed to room temperature and stirred for18 h, then quenched with water (50 mL) and extracted with DCM (3×50 mL).The organic layers were dried over anhydrous sodium sulfate andconcentrated in vacuo. The residue was purified by column chromatography(SiO₂, 100% DCM), yielding the title compound (8.3 g, 96%) as a yellowsolid. δ_(H) (d₆-DMSO) 7.16 (t, J 6.0 Hz, 1H), 8.45 (d, J 8.6 Hz, 1H),7.49 (d, J 8.5 Hz, 1H), 7.46-7.43 (m, 1H), 7.35 (dd, J 8.5, 2.6 Hz, 1H),6.83 (d, J 8.6 Hz, 1H), 4.72-4.69 (m, 2H). LCMS (ES⁺) 334.0 (M+H)⁺, RT1.71 minutes (Method B).

Intermediate 26-Chloro-N²-[(2,5-dichlorophenyl)methyl]pyridine-2,3-diamine

Zinc (5.1 g, 78.0 mmol) and saturated aqueous ammonium chloride solution(50 mL) were added to a stirred solution of Intermediate 1 (8.7 g, 26.0mmol) in EtOH (200 mL) at 0° C. The reaction mixture was heated at 50°C. for 2 h. The reaction mixture was filtered through a celite pad andconcentrated in vacuo. The residue was diluted with DCM (50 mL) andwashed with 2M aqueous NaOH solution (2×30 mL). The organic layers weredried over anhydrous sodium sulfate and concentrated in vacuo. Theresidue was purified by column chromatography (SiO₂, 0-5% EtOAc/DCM),yielding the title compound (5.8 g, 74%) as a purple solid. δ_(H)(d₆-DMSO) 7.49 (d, J 8.4 Hz, 1H), 7.19-7.17 (m, 3H), 6.76 (d, J 7.7 Hz,1H), 6.42 (d, J 7.7 Hz, 1H), 4.94 (s, 2H), 4.55 (d, J 5.6 Hz, 2H). LCMS(ES⁺) 304.0 (M+H)⁺, RT 1.54 minutes (Method B).

Intermediate 3 2-(4-Formylphenoxy)acetic acid

To a solution of 4-hydroxybenzaldehyde (10.0 g, 82.0 mmol) in acetone(150 mL) was added potassium carbonate (24.9 g, 180.0 mmol) and thereaction mixture was stirred at 40° C. for 15 minutes. Bromoacetic acid(12.0 g, 86.0 mmol) was added slowly, portionwise, and the reactionmixture was heated to reflux for 18 h. The reaction mixture was cooledand water (200 mL) was added. The reaction mixture was partitioned withEtOAc (2×200 mL), and the combined extracted aqueous layer was adjustedto pH 2 with 6N HCl. The aqeous layer was partitioned with EtOAc (2×400mL), then the organic layers were washed with water (200 mL), dried overanhydrous sodium sulfate and concentrated in vacuo. The residue wastriturated with isohexane to yield the title compound (13.5 g, 91%) as acream solid. δ_(H) (d₆-DMSO) 13.12 (br s, 1H), 9.87 (s, 1H), 7.88-7.85(m, 2H), 7.12-7.10 (m, 2H), 4.83 (s, 2H).

Intermediate 4 2-(4-Carbamoylphenoxy)acetic acid

To a solution of Intermediate 3 (1.9 g, 10.3 mmol) in formic acid (50mL) was added hydroxylamine hydrochloride (1.1 g, 15.5 mmol). Thereaction mixture was heated at reflux for 2 h, then cooled andconcentrated in vacuo. The residue was triturated with isohexane andfiltered. The resulting cream solid was suspended in tert-butanol (50mL), then potassium hydroxide (2.3 g, 41.0 mmol) was added and thereaction mixture was heated at reflux for 4 h. The reaction mixture wascooled and water (100 mL) was added. The reaction mixture waspartitioned with EtOAc (2×100 mL), and the combined extracted aqueouslayer was adjusted to pH 2 with 6N HCl. The resulting precipitate wasfiltered off and dried in vacuo, yielding the title compound (1.6 g,80%) as a white solid. δ_(H) (d₆-DMSO) 7.84-7.81 (m, 3H), 7.17 (br s,1H), 6.96-6.94 (m, 2H), 4.74 (s, 2H). LCMS (ES⁺) 196.0 (M+H)⁺, RT 0.30minutes (Method B).

Intermediate 55-Chloro-3-[(2,5-dichlorophenyl)methyl]-2-methylimidazo[4,5-b]pyridine

A solution of Intermediate 2 (0.4 g, 1.3 mmol) in acetic acid (5 mL) washeated at 140° C. for 18 h. The reaction mixture was cooled andconcentrated in vacuo. The residue was treated with 2M aqueous NaOHsolution (5 mL) and extracted with DCM (2×10 mL). The organic layerswere dried over anhydrous sodium sulfate and concentrated in vacuo. Theresidue was purified by column chromatography (SiO₂, 0-10% MeOH/DCM),yielding the title compound (0.6 g, 14%) as a cream solid. δ_(H)(d₆-DMSO) 8.08 (d, J 8.3 Hz, 1H), 7.61 (d, J 8.6 Hz, 1H), 7.49 (d, J 8.1Hz, 1H), 7.34 (d, J 8.3 Hz, 1H), 6.75 (d, J 2.5 Hz, 1H), 5.52 (s, 2H),2.30 (s, 3H). LCMS (ES⁺) 328.0 (M+H)⁺, RT 1.51 minutes (Method B).

Intermediate 66-Chloro-N-[(2,5-dimethylphenyl)methyl]-3-nitropyridin-2-amine

A suspension of 2,6-dichloro-3-nitropyridine (5 g, 25.9 mmol) in toluene(25 mL) was cooled to 0° C. and treated with 2,6-dimethylbenzylamine(4.2 g, 31 mmol). The resulting yellow suspension was stirred at 0° C.for 30 minutes, then sodium hydride (60% in mineral oil, 1.04 g, 26mmol) was added. The mixture was allowed to warm to room temperature andstirring was continued for 18 h. The resulting mixture was poured intowater (100 mL) and extracted with EtOAc (two portions of 100 mL each).The combined organic extracts were diluted with DCM (50 mL) and MeOH (20mL), then washed with brine (two portions of 70 mL each), dried overMgSO₄ and concentrated in vacuo. The resulting crude yellow solid wastriturated with diisopropyl ether to give a crude yellow solid (6.1 g).A portion of the crude material (800 mg) was further triturated withdiisopropyl ether to give the title compound (729 mg) as a yellow solid.HPLC-MS (pH 10): MH+m/z 292.3, RT 1.70 minutes.

Intermediate 76-Benzyloxy-N-[(2,5-dimethylphenyl)methyl]-3-nitropyridin-2-amine

A solution of benzyl alcohol (354 μL, 3.4 mmol) in DMF (4 mL) was cooledto 0° C. and treated with sodium hydride (60% in mineral oil, 136 mg,3.4 mmol). The reaction mixture was stirred for 5 minutes before theaddition of Intermediate 6 (500 mg, 1.71 mmol). The resulting mixturewas allowed to warm to room temperature over 1 h, then was diluted withwater (50 mL) and extracted with DCM (four portions of 50 mL each). Thecombined organic extracts were washed with brine (50 mL), dried overMgSO₄, filtered and concentrated in vacuo. The crude product wastriturated with diisopropyl ether to give the title compound (429 mg,96%) as a yellow solid. δ_(H) (DMSO-d₆) 9.13 (t, 1H), 8.34 (d, 1H), 7.30(s, 5H), 7.08 (m, 2H), 6.99 (d, 1H), 6.21 (d, 1H), 5.32 (s, 2H), 4.73(d, 2H), 2.28 (s, 3H), 2.20 (s, 3H).

Intermediate 86-Benzyloxy-N²-[(2,5-dimethylphenyl)methyl]pyridine-2,3-diamine

A suspension of Intermediate 7 (420 mg, 11.6 mmol) in ethanol (40 mL)was treated with ammonium chloride (saturated aqueous solution, 5 mL),followed by zinc powder (303 mg, 4.64 mmol), and the resulting mixturewas heated at reflux for 1.5 h. The mixture was filtered through celitewhilst warm, then concentrated in vacuo, to give a crude brown solidwhich was used in the subsequent step without further purification.

Intermediate 9 2-[(6-Carbamoylpyridin-3-yl)oxy]acetic acid

5-Hydroxypyridine-2-carboxylic acid methyl ester (5 g, 32 mmol) wassuspended in 7M NH₃ in MeOH (40 mL) and heated at 110° C. for 24 h in ahigh pressure reactor. The solvent was evaporated. The resulting darksolid (4.54 g) was dissolved in DMF (32 mL) and sodium hydride (60%dispersion in mineral oil, 1.37 g, 33.6 mmol) was added. The reactionmixture was stirred for 10 minutes, then tert-butyl bromoacetate (5.2mL, 35.2 mmol) was added. The reaction mixture was stirred for 4 h.Water (20 mL) was added. The resulting precipitate was filtered off anddried. The resulting material (3.73 g) was stirred in 4M HCl in1,4-dioxane (30 mL) for 5 h at room temperature. A portion (20%) of the1,4-dioxane was removed under vacuum, and the suspension was dilutedwith diethyl ether (30 mL). The resulting precipitate was filtered offand dried, to afford the title compound as the HCl salt (3.8 g, 61%),which was not purified further and was used crude in subsequent steps.

Intermediate 10 3-[(2,5-Dimethylphenyl)methyl]imidazo[4,5-b]pyridine

To a solution of 1H-imidazo[4,5-b]pyridine (1.9 g, 16 mmol) in THF (6mL) were added 2-(chloromethyl)-1,4-dimethylbenzene (2.6 g, 17 mmol) andpotassium carbonate (4.8 g, 35 mmol). The mixture was stirred overnightat room temperature. Water (5 mL) was added and the mixture was stirredfor another 10 minutes. The reaction mixture was poured into ethylacetate/water and the layers were separated. The organic layer waswashed three times with brine, then dried over magnesium sulphate andconcentrated in vacuo. The residue was purified by gradient silicacolumn chromatography, eluting with 0-60% ethyl acetate in DCM, followedby preparative chromatography, to afford the title compound (0.9 g, 24%)as a white solid. LCMS (ES+) (M+H)⁺ 238, RT 1.83 minutes (Method A).

Intermediate 11 6-Chloro-3-nitro-N-[(1R)-1-phenylethyl]pyridin-2-amine

To a solution of 2,6-dichloro-3-nitropyridine (1 g, 5.2 mmol) in THF (15mL) was added (1R)-1-phenylethanamine (0.7 mL, 5.2 mmol). After stirringfor 12 h at room temperature, the reaction mixture was quenched withwater (5 mL) and allowed to warm to ambient temperature. The reactionmixture was poured into ethyl acetate/water. The layers were separatedand the organic layer was washed three times with water, then dried overmagnesium sulphate and concentrated in vacuo. The residue was purifiedby gradient silica column chromatography, eluting with 0-10% ethylacetate in hexane, to afford the title compound (760 mg, 53%) as ayellow solid. δ_(H) (CDCl₃) 8.56 (d, J 6.2 Hz, 1H), 8.25 (d, J 14.9 Hz,1H), 7.57-7.23 (m, 4H), 7.22-7.19 (m, 1H), 6.52 (d, J 8.6 Hz, 1H), 5.41(q, J 14.1 Hz, 1H), 1.57 (d, J 6.9 Hz, 3H). LCMS (ES+) (M+H)⁺ 278, RT1.66 minutes (Method A).

Intermediate 126-(1-Methylpyrazol-4-yl)-3-nitro-N-[(1R)-1-phenylethyl]pyridin-2-amine

To a solution of Intermediate 11 (460 mg, 1.67 mmol) in ethanol (5 mL)were added 1-methylpyrazol-4-ylboronic acid (24 mg, 2.0 mmol) and Pd-118(5 mg, 0.005 mmol), followed by 2M aqueous Na₂CO₃ solution (2 mL). Themixture was degassed under nitrogen and heated under reflux for 2 h. Thereaction mixture was poured into ethyl acetate/water, washed four timeswith water, and dried over magnesium sulphate, then the solvent wasremoved by evaporation in vacuo. The residue was purified by gradientsilica column chromatography, eluting with 0-50% ethyl acetate in DCM,to afford the title compound (48 mg, 90%) as a yellow oil. δ_(H) (CDCl₃)8.69 (d, J 5.5 Hz, 1H), 8.38 (d, J 8.7 Hz, 1H), 7.91 (s, 1H), 7.77 (s,1H), 7.46-7.24 (m, 5H), 6.77 (d, J 8.7 Hz, 1H), 5.58-5.32 (m, 1H), 3.92(s, 3H), 1.68 (d, J 6.9 Hz, 3H). LCMS (ES+) (M+H)⁺ 324, RT 1.53 minutes(Method A).

Intermediate 136-(1-Methylpyrazol-4-yl)-N²-[(1R)-1-phenylethyl]pyridine-2,3-diamine

To a solution of Intermediate 12 (480 mg, 1.5 mmol) in ethanol (5 mL)and hydrochloric acid (10% aqueous solution, 2.5 mL) was added tinchloride (1.24 g, 4.5 mmol). The mixture was heated under reflux for 4h, then cooled to room temperature and quenched with 2N aqueous sodiumhydroxide solution (20 mL). EtOAc was added and the organic phase waswashed with brine. The organic layer was dried over magnesium sulfateand concentrated under reduced pressure. The crude residue (400 mg, 75%)was used directly in the next step. LCMS (ES+)(M+H)⁺ 294, RT 1.28minutes (Method A).

Intermediate 14 2,2-Dichloro-3-oxocyclobutyl 2,2-dimethylpropanoate

To a stirred mixture of vinyl pivalate (30 g, 234 mmol) and zinc (31 g,474 mmol) in diethyl ether (250 mL) was added a solution of2,2,2-trichloroacetyl chloride (34 mL, 304 mmol) in diethyl ether (250mL), dropwise over 2.5 h in a water bath, whilst maintaining thereaction temperature between 15° C. and 30° C. The reaction mixture wasfiltered through Celite and washed through with ethyl acetate (200 mL).The filtrate was washed with water (200 mL) and brine (200 mL), thendried over sodium sulfate and concentrated under vacuum, to afford thetitle compound (68 g, 97%) as an orange liquid. δ_(H) (500 MHz, CDCl₃)5.40 (dd, J 8.4, 6.2 Hz, 1H), 3.70 (dd, J 18.9, 8.4 Hz, 1H), 3.39 (dd, J18.9, 6.2 Hz, 1H), 1.28 (s, 9H).

Intermediate 15 3-Oxocyclobutyl 2,2-dimethylpropanoate

Zinc (74 g, 1.1 mol) was added to acetic acid (200 mL) with stirring andthe suspension was cooled in an ice bath. Intermediate 14 (68 g, 228mmol) in acetic acid (300 mL) was added dropwise over 2 h. Uponcompletion of addition, the reaction mixture was warmed to roomtemperature and stirred for 1.5 h, then filtered and washed with DCM(100 mL). The filtrate was diluted with EtOAc (800 mL) and washedsequentially with water (3×250 mL), saturated aqueous NaHCO₃ solution(3×250 mL) and brine (50 mL). The organic phase was dried over sodiumsulfate and concentrated in vacuo. The residue was purified bychromatography (SiO₂, 0-10% EtOAc in heptane), yielding the titlecompound (11 g, 28%) as a clear colourless oil. δ_(H) (500 MHz, CDCl₃)5.26-5.19 (m, 1H), 3.51-3.40 (m, 2H), 3.19-3.07 (m, 2H), 1.22 (s, 9H).

Intermediate 16 3-(5-Bromopyrimidin-2-yl)-3-hydroxycyclobutyl2,2-dimethylpropanoate

5-Bromo-2-iodopyrimidine (16.7 g, 58.8 mmol) was dissolved in DCM (200mL) with stirring and cooled to −78° C. under N₂. n-Butyllithium inhexane (2.5M, 23.5 mL) was added dropwise and the mixture was stirredfor 20 minutes at −78° C. Intermediate 15 (10 g, 58.8 mmol) in DCM (50mL) was cooled in a dry ice bath and added in one portion. The reactionmixture was stirred at −78° C. for 10 minutes, then quenched by theaddition of saturated aqueous NH₄Cl solution (20 mL) and allowed to warmto room temperature. Saturated aqueous NH₄Cl solution (50 mL) was addedand the mixture was extracted with DCM (2×100 mL). The combined organicextracts were dried over sodium sulfate and concentrated in vacuo. Thecrude residue was purified by column chromatography (SiO₂, 0-30% EtOAcin heptane), yielding the title compound (7.6 g, 35%) as a yellow solid.δ_(H) (500 MHz, CDCl₃) 8.78 (s, 2H), 5.22-5.14 (m, 1H), 3.03-2.93 (m,2H), 2.67-2.58 (m, 2H), 1.22 (s, 9H).

Intermediate 17 1-(5-Bromopyrimidin-2-yl)cyclobutane-1,3-diol

Intermediate 16 (6 g, 16.4 mmol) was dissolved in MeOH (120 mL) andK₂CO₃ (11.3 g, 82 mmol) was added. The reaction mixture was stirred for18 h at room temperature, then diluted with DCM (400 mL) and washed withwater (150 mL). The aqueous phase was extracted with DCM (200 mL). Thecombined organic extracts were dried over sodium sulfate andconcentrated in vacuo to afford the title compound (2.94 g, 73%) as anoff-white solid. δ_(H) (500 MHz, DMSO-d₆) 8.98 (s, 2H), 5.63 (s, 1H),5.08 (d, J 6.2 Hz, 1H), 4.09-3.92 (m, 1H), 2.87-2.79 (m, 2H), 2.28-2.14(m, 2H).

Intermediate 18 3-(5-Bromopyrimidin-2-yl)-3-hydroxycyclobutan-1-one

To a stirred solution of Intermediate 17 (2 g, 8.1 mmol) in DCM (200 mL)was added Dess-Martin periodinane (4.1 g, 9.8 mmol). The reactionmixture was stirred for 18 h and the resulting suspension was dilutedwith DCM (100 mL), then washed with saturated aqueous NaHCO₃ solution(100 mL). The aqueous layer was re-extracted with DCM (100 mL), then thecombined organic extracts were dried over sodium sulfate andconcentrated in vacuo. The crude residue was purified by chromatography(SiO₂, 0-30% EtOAc in heptane) to afford the title compound (1.37 g,69%) as an off white solid. δ_(H) (500 MHz, DMSO-d₆) 9.04 (s, 2H), 6.41(s, 1H), 3.69-3.55 (m, 2H), 3.37-3.21 (m, 2H).

Intermediate 193-(5-Bromopyrimidin-2-yl)-3-[(tert-butyldimethylsilyl)oxy]cyclobutan-1-one

Intermediate 18 (1.37 g, 5.64 mmol) was dissolved in anhydrous DMF (20mL) with stirring under N₂ and cooled to 0° C. 1H-Imidazole (1.9 g,28.18 mmol) was added, followed by tert-butyl(chloro)dimethylsilane (2.0g, 13.5 mmol). The reaction mixture was stirred at room temperature for20 h, then diluted with DCM (150 mL) and washed with water (3×50 mL).The aqueous phase was re-extracted with DCM (50 mL). The combinedorganic extracts were dried over sodium sulfate and concentrated invacuo. The crude residue was purified by chromatography (SiO₂, 0-20%EtOAc in heptane) to afford the title compound (1.6 g 79%) as a paleorange oil. δ_(H) (500 MHz, DMSO-d₆) 9.06 (s, 2H), 3.78-3.66 (m, 2H),3.44-3.34 (m, 2H), 0.88 (s, 9H), 0.00 (s, 6H).

Intermediate 203-(5-Bromopyrimidin-2-yl)-3-[(tert-butyldimethylsilyl)oxy]-1-methylcyclobutan-1-ol

Intermediate 19 (1.35 g, 3.78 mmol) was dissolved in anhydrous diethylether (40 mL) under N₂ with stirring and cooled to 0° C. using an icebath. Methylmagnesium bromide in diethyl ether (3M, 2.52 mL) was addeddropwise. The reaction mixture was stirred for 30 minutes at 0° C., thenquenched with saturated aqueous NH₄Cl solution (20 mL) and water (20mL). The mixture was extracted with EtOAc (2×50 mL), dried over sodiumsulfate and concentrated in vacuo. The crude residue was purified bychromatography (SiO₂, 0-100% DCM in heptane) to afford the titlecompound (1.19 g, 84%) as a clear oil. Major isomer (˜70% abundance):δ_(H) (500 MHz, CDCl₃) 8.79 (s, 2H), 3.10-3.03 (m, 2H), 2.59-2.51 (m,2H), 1.18 (s, 3H), 0.87 (s, 9H), −0.14 (s, 6H). Minor isomer (˜30%abundance): δ_(H) (500 MHz, CDCl₃) 8.79 (s, 2H), 2.78-2.63 (m, 4H), 1.49(s, 3H), 0.95 (s, 9H), 0.04 (s, 6H).

Intermediate 212-[5-(6-Amino-5-nitropyridin-2-yl)pyrimidin-2-yl]propan-2-ol

Prepared from2-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl]-propan-2-ol(4.19 g, 15.85 mmol), 6-bromo-3-nitropyridin-2-amine (3.00 g, 13.21mmol), cesium carbonate (6.45 mg, 19.82 mmol), 1,4-dioxane/watersolution (9:1, 50 mL) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (483.3 mg, 5mol %) in accordance with Method A to give the title compound (3.03 g,73%). δ_(H) (400 MHz, CDCl₃) 9.31 (s, 2H), 8.57 (d, J 8.6 Hz, 1H), 7.21(d, J 8.6 Hz, 1H), 4.60 (s, 1H), 1.89 (br s, 1H), 1.64 (s, 6H). LCMS(ES⁺) 276.14 (M+H)⁺, RT 3.54 minutes.

Intermediate 22N-{6-[2-(1-Hydroxy-1-methylethyl)pyrimidin-5-yl]-3-nitropyridin-2-yl}acetamide

To a solution of Intermediate 21 (3.47 g, 10.1 mmol) in acetic acid (10mL) were added acetic anhydride (10 mL) and sulfuric acid (260 pt, 4.88mmol). The mixture was stirred at 65° C. for 1 h, then cooled to roomtemperature. The white solid was filtered off and washed with DCM (150mL). The filtrate was neutralized by saturated aqueous NaHCO₃ solution,then the mixture was partitioned and the aqueous layer was extractedwith DCM (3×50 mL). The combined organic layers were dried over MgSO₄,filtered and concentrated in vacuo. The residue was purified by columnchromatography (SiO₂, 99.5:0.45:0.05 DCM/MeOH/NH₄OH), yielding the titlecompound (1.5 g, 47%). LCMS (ES⁺) 318.22 (M+H)⁺, RT 4.10 minutes.

Intermediate 23 (Method B)N-{[2-(Difluoromethoxy)phenyl]methyl}-N-{6-[2-(1-hydroxy-1-methylethyl)pyrimidin-5-yl]-3-nitropyridin-2-yl}acetamide

To a suspension of Intermediate 22 (200 mg, 0.5043 mmol) and2-(difluoromethoxy)benzyl bromide (153 mg, 0.65 mmol) in acetonitrile (4mL) were added DMF (0.4 mL) and Cs₂CO₃ (328.6 mg, 1.01 mmol). Thereaction mixture was stirred at room temperature overnight, thenconcentrated in vacuo. The residue was taken up in water (10 mL) andethyl acetate (10 mL). The aqueous layer was extracted with ethylacetate (3×10 mL). The combined organic layers were washed with water(2×10 mL) and saturated aqueous NH₄Cl solution (10 mL), then dried overMgSO₄ and concentrated in vacuo. The crude residue was used withoutfurther purification. LCMS (ES⁺) 474.0 (M+H)⁺, RT 3.14 minutes.

Intermediate 24N-{3-Amino-6-[2-(1-hydroxy-1-methylethyl)pyrimidin-5-yl]pyridin-2-yl}-N-{[2-(difluoromethoxy)phenyl]methyl}acetamide

Pt/C 5% type 5R163 (5.08 mg, 2 wt %) was added to a solution ofIntermediate 23 (254 mg, 0.54 mmol) in 1,4-dioxane (1.1 mL) and themixture was stirred for 2 days at room temperature under H₂ (5 bar). Thesolution was filtered through 45μ Whatman filters, then concentrated invacuo, yielding the title compound (239 mg, quantitative), which wasused without further purification. LCMS (ES⁺) 444.0 (M+H)⁺, RT 2.79minutes.

Intermediate 25 [2-Bromo-6-(difluoromethoxy)phenyl]methanol

2-Bromo-6-(difluoromethoxy)benzaldehyde (12.0 g, 47.8 mmol) wasdissolved in MeOH (20 mL). The reaction mixture was cooled to −15° C.,then sodium borohydride (1.81 g, 47.8 mmol) was added cautiously. Thereaction mixture was stirred for 10 minutes, then treated with NH₄Cl andpartitioned with EtOAc. The organic layers were extracted and washedwith brine, then dried over MgSO₄ and concentrated in vacuo, yieldingthe title compound (12.46 g, quantitative) as a brown oil. δ_(H) (400MHz, DMSO-d₆) 7.53 (dd, J 8.0, 1.0 Hz, 1H), 7.32 (t, J 8.2 Hz, 1H), 7.23(dd, J 8.2, 0.7 Hz, 1H), 7.17 (t, J 74.2 Hz, 1H), 5.10 (s, 1H), 4.61 (s,2H).

Intermediate 26 1-Bromo-2-(bromomethyl)-3-(difluoromethoxy)benzene

Intermediate 25 (12.46 g, 49.24 mmol) was dissolved in DCM (200 mL) andcooled to 0° C. Carbon tetrabromide (24.49 g, 73.86 mmol) andtriphenylphosphine (19.37 g, 73.86 mmol) were added. The reactionmixture was stirred for 10 minutes, then treated with water andpartitioned. The organic layers were extracted and dried over MgSO₄,then concentrated in vacuo. The residue was purified by chromatography(SiO₂, 0-20% EtOAc in hexane) to give the title compound (15.41 g,quantitative) as a brown oil. δ_(H) (400 MHz, DMSO-d₆) 7.57 (dd, J 8.1,1.0 Hz, 1H), 7.39 (t, J 8.2 Hz, 1H), 7.34 (t, J 73.2 Hz, 1H), 7.28 (dd,J 8.3, 0.7 Hz, 1H), 4.69 (s, 2H).

Intermediate 27N-{[2-Bromo-6-(difluoromethoxy)phenyl]methyl}-N-{6-[2-(1-hydroxy-1-methylethyl)-pyrimidin-5-yl]-3-nitropyridin-2-yl}acetamide

Prepared from Intermediate 22 (900 mg, 2.84 mmol), Intermediate 26 (1.19mg, 3.69 mmol), acetonitrile (25 mL), DMSO (2.3 mL) and Cs₂CO₃ (1.85 mg,5.67 mmol) in accordance with Method B to give the title compound (911mg, 52%). δ_(H) (400 MHz, DMSO-d₆) 9.49 (s, 2H), 8.59 (d, J 8.5 Hz, 1H),8.56 (t, J 5.8 Hz, 1H), 7.61 (d, J 8.0 Hz, 1H), 7.55 (dd, J 5.8, 5.0 Hz,1H), 7.39 (t, J 8.0 Hz, 1H), 7.30 (d, J 8.5 Hz, 1H), 7.26 (t, J 73.3 Hz,1H), 5.15 (d, J 5.0 Hz, 2H), 2.01 (s, 3H), 1.74 (s, 6H). LCMS (ES+)552.0/554.0 (M+H)⁺, RT 5.60 minutes.

Intermediate 286-Chloro-N-{[2-(difluoromethoxy)-6-fluorophenyl]methyl}-3-nitropyridin-2-amine

Potassium carbonate (19.10 g, 138.2 mmol) was added to a suspension of2,6-dichloro-3-nitropyridine (25 g, 125.65 mmol) and[2-(difluoromethoxy)-6-fluorophenyl]-methanamine (26.42 g, 138.22 mmol)in acetonitrile (200 mL). The reaction mixture was stirred at roomtemperature for 2 h, then partitioned between water and DCM. The organiclayer was washed with water and dried over MgSO₄, then filtered andconcentrated in vacuo. The resulting crystalline solid was taken up in aminimum amount of diethyl ether and filtered, then washed with a smallamount of diethyl ether and dried, yielding the title compound (27 g,62%) as a yellow solid. δ_(H) (400 MHz, DMSO-d₆) 8.79 (t, J 5.5 Hz, 1H),8.43 (d, J 8.6 Hz, 1H), 7.43 (m, 1H), 7.28 (t, J 76 Hz, 1H), 7.15 (m,1H), 7.08 (d, J 8.3 Hz, 1H), 6.83 (d, J 8.6 Hz, 1H), 4.83 (d, J 5.7 Hz,2H). LCMS (ES+) 348.0 (M+H)⁺, RT 1.54 minutes.

Intermediate 296-Chloro-N²-{[2-(difluoromethoxy)-6-fluorophenyl]methyl}pyridine-2,3-diamine

A mixture of Intermediate 28 (25 g, 71.90 mmol) and 5% Pt/C 163 (2.5 g,10 wt %) in EtOAc (350 mL) was de-gassed and flushed with hydrogen, thenhydrogenated at normal pressure at room temperature for 18 h. Morecatalyst (0.5 g) was added, then the reaction mixture was de-gassed andhydrogenated for a further 18 h. The mixture was filtered through a plugof celite-silica gel, washing with EtOAc. The residue was crystallisedfrom diethyl ether/hexane and filtered, then washed with hexane/diethylether (2:1) and dried, yielding the title compound (22.4 g, 98%) as agreen solid. δ_(H) (400 MHz, DMSO-d₆) 7.44 (m, 1H), 7.25 (t, J 76 Hz,1H), 7.16 (m, 1H), 7.08 (m, 1H), 6.69 (d, J 7.7 Hz, 1H), 6.40 (d, J 7.7Hz, 1H), 5.97 (t, J 4.6 Hz, 1H), 4.90 (s, 2H), 4.46 (d, J 4.0 Hz, 2H).LCMS (ES⁺) 318.0 (M+H)⁺, RT 1.47 minutes.

Intermediate 305-Chloro-3-{[2-(difluoromethoxy)-6-fluorophenyl]methyl}-2-methylimidazo[4,5-b]-pyridine

Intermediate 29 (20 g, 62.95 mmol) was divided into batches (4×5 g).Each batch was dissolved in acetic acid (25 mL) and heated undermicrowave irradiation at 150° C. for 8 h. The batches were combined andconcentrated in vacuo. The residue was dissolved in EtOAc and washedtwice with saturated aqueous NaHCO₃ solution. The organic extract wasdried over MgSO₄, filtered through celite/silica gel (EtOAc) andconcentrated in vacuo. The brown solid was slurried in diethyl ether andfiltered, then washed with diethyl ether and dried, to yield the titlecompound (12.5 g, 58%) as a light brown solid. δ_(H) (400 MHz, DMSO-d₆)7.96 (d, J 8.3 Hz, 1H), 7.48 (m, 1H), 7.25 (m, 2H), 7.15 (m, 1H), 7.08(m, 1H), 5.47 (s, 2H). LCMS (ES⁺) 342 (M+H)⁺, RT 1.44 minutes.

Intermediate 313-[tert-Butyl(dimethyl)silyl]oxy-3-[5-(3-{[2-(difluoromethoxy)-6-fluorophenyl]methyl}-2-methylimidazo[4,5-b]pyridin-5-yl)pyrimidin-2-yl]-1-methylcyclobutanol

A mixture of Intermediate 20 (200 mg, 0.53 mmol), bis(pinacolato)diboron(166.5 mg, 0.64 mmol) and potassium acetate (162.6 mg, 1.607 mmol) in1,4-dioxane (5 mL) was purged with argon.[1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II)-dichloromethanecomplex (12.38 mg, 0.016 mmol, 3 mol %) was added and the reactionmixture was stirred at 100° C. under an argon atmosphere for 1 h, thencooled to room temperature. Water (2.5 mL) was added, followed byIntermediate 30 (201.3 mg, 0.59 mmol) and sodium carbonate (113.6 mg,1.07 mmol). The mixture was purged with argon, then Pd₂(dba)₃ (9.81 mg,0.03 mmol, 2 mol %) and tri(tert-butyl)phosphonium tetrafluoroborate(6.22 mg, 0.02 mmol, 4 mol %) were added. The reaction mixture washeated under argon for 3 h at 90° C. The mixture was cooled to roomtemperature and partitioned between EtOAc (15 mL) and water (15 mL),then extracted with EtOAc (3×10 mL). The combined organic layers weresuccessively washed with saturated aqueous NH₄Cl solution and saturatedaqueous NaHCO₃ solution, then dried over MgSO₄, filtered andconcentrated in vacuo. The crude residue was purified by columnchromatography (SiO₂, gradient 0-100% EtOAc in heptane), yielding thetitle compound (215 mg, 67.0%). LCMS (ES⁺) 600.0 (M+H)⁺, RT 2.97minutes.

Intermediate 32 3-Bromo-2-fluoro-6-methoxybenzaldehyde

To a solution of 1-bromo-2-fluoro-4-methoxybenzene (25 g, 121.9 mmol) inTHF (250 mL) at −78° C. was added LDA (2M solution in THF; 73.2 mL,146.3 mmol) and the reaction mixture was stirred for 10 minutes. DMF (11mL, 146.34 mmol) was added and the reaction mixture was allowed to warmto room temperature. After completion of the reaction (monitored byTLC), the reaction mixture was quenched with saturated aqueous ammoniumchloride solution and the residue was extracted with EtOAc. The organiclayer was washed with water and brine, then dried over sodium sulphateand concentrated in vacuo. The crude residue was purified by columnchromatography (SiO₂, gradient 0-20% EtOAc in hexane), yielding thetitle compound as a pale yellow solid (25.5 g, 89%). δ_(H) (400 MHz,CDCl₃) 10.38 (s, 1H), 7.67 (t, J 8.35 Hz, 1H), 6.72 (d, J 9.03 Hz, 1H),3.93 (s, 3H).

Intermediate 33 3-Bromo-2-fluoro-6-hydroxybenzaldehyde

To a solution of Intermediate 32 (50 g, 215.5 mmol) in dry DCM (300 mL)at −50° C. was added boron tribromide (1M solution in DCM; 646 mL, 646mmol). The reaction mixture was stirred at −50° C. for 30 minutes, thendiluted with water. The organic layer was separated, then washed withwater and brine. The organic layer was separated and dried over sodiumsulphate, then concentrated in vacuo, to yield the title compound (40 g,85%) as a white solid. δ_(H) (400 MHz, CDCl₃) 11.44 (s, 1H), 10.23-10.38(m, 1H), 7.63 (t, J 8.35 Hz, 1H), 6.73 (d, J 9.03 Hz, 1H).

Intermediate 34 3-Bromo-6-(difluoromethoxy)-2-fluorob enz aldehyde

To a solution of Intermediate 33 (40 g, 183.5 mmol) in acetonitrile (200mL) at 0° C. were added aqueous KOH (61.6 g, 1100 mmol) and diethyl[bromo(difluoro)methyl]-phosphonate (52.2 mL, 293.6 mmol). The reactionmixture was stirred at 0° C. for 30 minutes, then quenched with water.The residue was extracted with EtOAc. The organic layer was washed withwater and brine, then separated, dried over sodium sulphate andconcentrated in vacuo. The crude residue was purified by columnchromatography (SiO₂, gradient 0-5% EtOAc in hexane), yielding the titlecompound (20 g, 41%) as a yellow oil. δ_(H) (400 MHz, CDCl₃) 10.34 (s,1H), 7.78 (t, J 8.13 Hz, 1H), 6.98-7.08 (m, 1H), 6.42-6.85 (m, 1H).

Intermediate 35 [3-Bromo-6-(difluoromethoxy)-2-fluorophenyl]methanol

To a solution of Intermediate 34 (20 g, 74.6 mmol) in MeOH (200 mL) at−15° C. was added sodium borohydride (2.76 g, 74.6 mmol). The reactionmixture was stirred at −15° C. for 20 minutes, then quenched withice-cold water and concentrated in vacuo. The residue was extracted withDCM and washed with water. The organic layer was separated and driedover sodium sulphate, then concentrated in vacuo, to yield the titlecompound (17.5 g, 87%) as a clear oil. δ_(H) (400 MHz, CDCl₃) 7.47-7.57(m, 1H), 6.91 (d, J 8.58 Hz, 1H), 6.38-6.78 (m, 1H), 4.80 (s, 2H).

Intermediate 361-Bromo-3-(bromomethyl)-4-(difluoromethoxy)-2-fluorobenzene

To a solution of Intermediate 35 (17.5 g, 64.81 mmol) in DCM (200 mL) at0° C. were added carbon tetrabromide (32.2 g, 97.22 mmol) andtriphenylphosphine (25.5 g, 97.22 mmol). The reaction mixture wasstirred at 0° C. for 10 minutes, then quenched with ice-cold water. Theresidue was extracted with DCM. The organic layer was separated anddried over sodium sulphate, then concentrated in vacuo, to yield thetitle compound (16.3 g, 76%) as a white solid. δ_(H) (400 MHz, CDCl₃)7.53 (t, J 8.13 Hz, 1H), 6.92 (d, J 8.58 Hz, 1H), 6.37-6.79 (m, 1H),4.55 (s, 2H).

Intermediate 372-[5-(6-{[3-Bromo-6-(difluoromethoxy)-2-fluorophenyl]methylamino}-5-nitropyridin-2-yl)pyrimidin-2-yl]propan-2-ol

To a solution of Intermediate 21 (2.52 g, 9.15 mmol) in acetonitrile (73mL) were added Intermediate 36 (4.58 g, 13.72 mmol), DMF (7.3 mL) andCs₂CO₃ (5.96 g, 18.31 mmol). The reaction mixture was stirred at roomtemperature for 18 h, then concentrated in vacuo. Water was added andthe mixture was extracted with EtOAc. The organic layers were washedwith saturated aqueous NH₄Cl solution, dried over MgSO₄ and concentratedin vacuo, yielding the title compound (4.8 g, quantitative) as a yellowsolid. LCMS (ES+) 528.0/530.0 (M+H)⁺, RT 3.14 minutes.

Intermediate 382-[5-(5-Amino-6-{[3-bromo-6-(difluoromethoxy)-2-fluorophenyl]methylamino}pyridin-2-yl)pyrimidin-2-yl]propan-2-ol

Pt/C 5% type 5R163 (122 mg, 2 wt %) was added to a solution ofIntermediate 37 (6.10 g, 0.54 mmol) in 1,4-dioxane (23 mL) and themixture was stirred for 2 days at room temperature under H₂ (5 bar). Thesolution was filtered through 45μ Whatman filters and concentrated invacuo. The crude residue was purified by column chromatography (SiO₂,gradient 0-100% EtOAc in heptane), yielding the title compound (2.95 g,51%). LCMS (ES⁺) 498.0/500.0 (M+H)⁺, RT 3.16 minutes.

Intermediate 39N-[(5-Bromopyridin-2-yl)(methyl)(oxo)-λ⁶-sulfanylidene]-2,2,2-trifluoroacetamide

To a suspension of 5-bromo-2-(methylsulfinyl)pyridine (5 g, 22.8 mmol),MgO (3.68 g, 91.3 mmol), tetrakis(acetato-κO)dirhodium(Rh—Rh) (0.25 g,0.570 mmol) and 2,2,2-trifluoroacetamide (5.16 g, 45.6 mmol) inanhydrous DCM (150 mL) was added bis(acetyloxy)(phenyl)-λ³-iodane (11.03g, 34.2 mmol) at room temperature. The reaction mixture was stirred atroom temperature for 18 h, then filtered over celite. The filter cakewas washed with DCM (30 mL). The filtrate was concentrated in vacuo andpurified by column chromatography (SiO₂, 0-100% EtOAc in heptane),yielding the title compound (5.7 g, 97%) as a light yellow oil. LCMS(ES⁺) 332.0/334.0 (M+H)⁺, RT 1.27 minutes.

Example 14-({5-Chloro-3-[(2,5-dichlorophenyl)methyl]imidazo[4,5-b]pyridin-2-yl}methoxy)-benzamide

To a solution of Intermediate 2 (2.9 g, 9.6 mmol) in DMF (30 mL) wereadded Intermediate 4 (2.2 g, 11.3 mmol), EDCI (2.18 g, 11.5 mmol), HOBT(1.75 g, 11.3 mmol) and DIPEA (3.3 mL, 19.2 mmol). The reaction mixturewas stirred at room temperature for 18 h. The reaction mixture wastreated with brine (20 mL) and EtOAc (2×20 mL). The combined organiclayers were dried over anhydrous sodium sulfate and concentrated invacuo. The residue was suspended in 1,4-dioxane (10 mL) and PTSA (1.42g, 8.2 mmol) was added, then the reaction mixture was heated at refluxfor 2 h. The reaction mixture was cooled and treated with 2M aqueousNaOH solution (5 mL), then extracted with DCM (2×10 mL). The organiclayers were dried over anhydrous sodium sulfate and concentrated invacuo. The residue was purified by column chromatography (SiO₂, 0-100%EtOAc/DCM), yielding the title compound (0.2 g, 5%) as a cream solid.δ_(H) (d₆-DMSO) 8.28 (d, J 8.4 Hz, 1H), 7.78 (m, 3H), 7.57 (d, J 8.6 Hz,1H), 7.46 (d, J 8.4 Hz, 1H), 7.40 (dd, J 8.6, 2.5 Hz, 1H), 7.18 (s, 1H),6.83 (d, J 8.9 Hz, 2H), 6.58 (d, J 2.5 Hz, 1H), 5.64 (s, 2H), 5.49 (s,2H). LCMS (ES⁺) 463.0 (M+H)⁺, RT 2.43 minutes (Method C).

Example 2 (Method A)4-({3-[(2,5-Dichlorophenyl)methyl]-5-(pyridin-4-yl)imidazo[4,5-b]pyridin-2-yl}-methoxy)benzamide

A microwave vial was charged with a solution of Example 1 (0.2 g, 0.3mmol) in 1,4-dioxane (3 mL) and water (1 mL). Pyridin-4-ylboronic acid(0.05 g, 0.42 mmol) and 2M aqueous sodium carbonate solution (1 mL) wereadded, and the reaction mixture was degassed for 10 minutes. Pd(PPh₃)₄(0.04 g, 0.10 mmol) was added and the reaction mixture was degassed for10 minutes, then heated at 100° C. for 60 minutes in a Biotage microwavereactor. Ethyl acetate was added to the reaction mixture, and themixture was filtered through a Celite pad. The organic layer wasseparated, dried over anhydrous sodium sulphate, and concentrated invacuo. The residue was purified by preparative HPLC, yielding the titlecompound (1 mg, 8%) as a white solid. δ_(H) (d₆-DMSO) 8.68 (dd, J 5.1,1.6 Hz, 2H), 8.33 (d, J 8.4 Hz, 1H), 8.13 (d, J 8.3 Hz, 1H), 8.06 (dd, J4.6, 1.6 Hz, 2H), 7.83 (s, 1H), 7.81 (d, J 8.9 Hz, 2H), 7.57 (d, J 8.6Hz, 1H), 7.40 (dd, J 8.6, 2.5 Hz, 1H), 7.22 (s, 1H), 6.92-6.89 (m, 3H),5.77 (s, 2H), 5.57 (s, 2H). LCMS (ES⁺) 504.0 (M+H)⁺, RT 2.14 minutes(Method C).

Example 33-[(2,5-Dichlorophenyl)methyl]-2-methyl-5-(pyridin-4-yl)imidazo[4,5-b]pyridine

Prepared from Intermediate 5 (0.06 g, 0.18 mmol) and pyridin-4-ylboronicacid (0.03 g, 0.22 mmol) in accordance with Method A to give the titlecompound (4 mg, 6%). δ_(H) (d₆-DMSO) 8.66 (d, J 6.0 Hz, 2H), 8.12 (d, J8.3 Hz, 1H), 8.05-8.01 (m, 3H), 7.58 (d, J 8.6 Hz, 1H), 7.45 (dd, J 8.6,2.5 Hz, 1H), 7.14 (d, J 8.6 Hz, 1H), 5.63 (s, 2H), 2.62 (s, 3H). LCMS(ES⁺) 371.0 (M+H)⁺, RT 2.17 minutes (Method C).

Example 45-Benzyloxy-3-[(2,5-dimethylphenyl)methyl]-2-methylimidazo[4,5-b]pyridine

A suspension of Intermediate 8 (400 mg, 1.2 mmol) in acetic acid (5 mL)was heated at reflux for 3 days, then allowed to cool to roomtemperature. The crude mixture was concentrated in vacuo, then theresidue was partitioned between EtOAc (50 mL) and Na₂CO₃ (10% w/vaqueous solution, 30 mL). The aqueous phase was extracted with EtOAc (30mL), then the combined organic extracts were washed with brine (50 mL)and dried over MgSO₄. Filtration and concentration in vacuo gave a crudegum which was purified by column chromatography on SiO₂, eluting withDCM:EtOAc (gradient from 0 to 30% EtOAc), and trituration withdiisopropyl ether, to yield the title compound (30 mg, 67%) as anoff-white powder. δ_(H) (DMSO-d₆) 7.90 (d, 1H), 7.38-7.41 (m, 2H),7.27-7.28 (m, 3H), 7.13 (d, 1H), 7.00 (d, 1H), 6.69 (d, 1H), 6.36 (s,1H), 5.38 (s, 2H), 5.32 (s, 2H), 2.39 (s, 3H), 2.33 (s, 3H), 2.10 (s,3H). LCMS (ES⁺) 358.8 (M+H)⁺, RT 2.77 minutes (Method A).

Example 55-({5-Benzyloxy-3-[(2,5-dimethylphenyl)methyl]imidazo[4,5-b]pyridin-2-yl}methoxy)-pyridine-2-carboxamide

A suspension of Intermediate 9 (470 mg, 2.4 mmol) in DCM (5 mL) wastreated with DMF (2 mL), followed by HATU (912 mg, 2.4 mmol) and DIPEA(420 μL, 2.4 mmol), and the mixture was stirred at room temperature for5 minutes. The mixture was treated with Intermediate 8 (730 mg, 2.1mmol) in DCM (5 mL), then stirred at room temperature for 18 h. Thereaction mixture was treated with water (20 mL) and extracted with DCM(two portions of 25 mL each), then the combined organic layers wereconcentrated in vacuo. The residue was taken up in acetic acid (25 mL)and heated at reflux for 8 h. The reaction mixture was concentrated invacuo and the residue was partitioned between DCM (60 mL) and Na₂CO₃(10% w/v aqueous solution, 50 mL). The aqueous phase was furtherextracted with DCM/EtOAc (9:1 mixture, two portions of 50 mL each). Thecombined organic extracts were washed with brine (two portions of 40 mLeach), dried over MgSO₄ and concentrated in vacuo. The crude residue waspurified by column chromatography on SiO₂ (eluting with DCM/EtOAc,gradient from 1:0 to 0:1), followed by trituration with EtOAc, to yieldthe title compound (180 mg, 17%) as a pale solid. δ_(H) (DMSO-d₆)8.07-8.09 (m, 2H), 7.94 (d, 1H), 7.92 (s, 1H), 7.45-7.48 (m, 2H),7.37-7.40 (m, 2H), 7.26-7.28 (m, 3H), 7.08 (d, 1H), 6.95 (d, 1H), 6.80(d, 1H), 6.34 (s, 1H), 5.51 (s, 2H), 5.39 (s, 2H), 5.35 (s, 2H), 2.23(s, 3H), 1.90 (s, 3H). LCMS (ES⁺) 494.8, RT 2.64 minutes (Method A).

Example 6{3-[(2,5-Dimethylphenyl)methyl]imidazo[4,5-b]pyridin-2-yl}(phenyl)methanol

To a solution of Intermediate 10 (380 mg, 1.6 mmol) in THF (10 mL) at−78° C. was added 1.6M n-butyllithium in hexane (3.2 mmol) over 1minute. The reaction mixture was stirred for 20 minutes, thenbenzaldehyde (0.34 g, 3.2 mmol) in THF (2 mL) was added over 1 minute.After a further 10 minutes, the reaction mixture was quenched with water(lmL) and allowed to warm to ambient temperature. The reaction mixturewas poured into ethyl acetate/water. The layers were separated and theorganic layer was washed three times with water, then dried overmagnesium sulphate and concentrated under vacuum. The residue waspurified by gradient silica column chromatography, eluting with 0-60%ethyl acetate in DCM, followed by preparative chromatography, to affordthe title compound (300 mg, 55%) as a white solid. δ_(H) (CDCl₃) 8.33(d, J 4.8 Hz, 1H), 7.88 (dd, J 8.0, 1.3 Hz, 1H), 7.25-7.15 (m, 7H),7.05-7.00 (m, 1H), 7.00-6.90 (m, 1H), 6.91 (s, 1H), 5.82 (s, 1H), 5.25(dd, J_(AB) 16.8 Hz, 2H), 2.17 (s, 3H), 2.02 (s, 3H). LCMS (ES⁺) 344.0(M+H)⁺, RT 2.24 minutes (Method C).

Example 7{5-(1-Methylpyrazol-4-yl)-3-[(1R)-1-phenylethyl]imidazo[4,5-b]pyridin-2-yl}methanol

A mixture of Intermediate 13 (400 mg, 1.36 mmol), glycolic acid (125 mg,1.6 mmol), HATU (573 mg, 1.5 mmol) and triethylamine (0.38 mL, 2.7 mmol)in DCM (15 mL) was stirred at room temperature for 2 h. The cooledreaction mixture was diluted with EtOAc and washed with brine. Theorganic layer was dried over magnesium sulfate and concentrated underreduced pressure. The crude residue was retaken in acetic acid (5 mL)and heated at 140° C. for 4 h, then cooled down to room temperature. Themixture was concentrated under reduced pressure, retaken in DCM andwashed with 2M aqueous NaOH solution. The organic layer was dried overmagnesium sulfate and concentrated under reduced pressure. The cruderesidue was redissolved in a mixture of THF, methanol and 2M aqueousNaOH solution, then heated at 65° C. for 1 h. The cooled reactionmixture was diluted with EtOAc and washed with brine. The organic layerwas dried over magnesium sulfate and concentrated under reducedpressure. The crude residue was purified by column chromatography (SiO₂,EtOAc:DCM, 80 to 100%) to give the title compound (115 mg, 25%) as awhite solid. δ_(H) (CDCl₃) 8.00 (s, 1H), 8.00-7.90 (m, 2H), 7.45-7.30(m, 6H), 6.22 (q, J 14.4, 7.0 Hz), 4.65 (dd, J 15.8, 5.6 Hz, 2H), 4.00(s, 3H), 3.25 (t, J 5.8 Hz, 1H), 2.11 (d, J 7.2 Hz, 3H). LCMS (ES⁺)334.0 (M+H)⁺, RT 1.64 minutes (Method C).

Example 82-(5-{3-[2-(Difluoromethoxy)benzyl]-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl}-pyrimidin-2-yl)propan-2-ol

Intermediate 24 (254 mg, 0.5728 mmol) was dissolved in 1,4-dioxane (2.5mL) and acetic anhydride (0.06 mL) was added. The mixture was stirred at80° C. for 1 h, then the solvent was removed in vacuo. The residue wastaken up in acetic acid (2 mL) and heated at 150° C. for 2 h. The aceticacid was stripped with toluene (3×5 mL). The residue was taken up inEtOAc and washed with saturated aqueous NaHCO₃ solution. The organiclayer was dried over MgSO₄, filtered and concentrated in vacuo. Theresidue was dissolved in MeOH (1.2 mL) and cooled in an ice bath, thenaqueous NaOH solution (1N, 0.25 mL) was added. The mixture was stirredovernight and allowed to warm slowly to room temperature, thenconcentrated in vacuo. The residue was taken up in the minimum volume ofacetonitrile/water (70:30), with a drop of DMSO, and purified bypreparative HPLC, yielding the title compound (10 mg, 18%) as anoff-white solid. δ_(H) (400 MHz, CDCl₃) 9.33 (s, 2H), 8.08 (d, J 8.2 Hz,1H), 7.69 (d, J 8.2 Hz, 1H), 7.33 (dt, J 8.0, 1.5 Hz, 1H), 7.18 (dd, J8.0, 1.0 Hz, 1H), 7.12 (td, J 7.7, 1.0 Hz, 1H), 6.99 (dd, J 7.7, 1.5 Hz,1H), 6.65 (t, J 73.3 Hz, 1H), 5.60 (s, 2H), 4.72 (s, 1H), 2.61 (s, 3H),1.64 (s, 6H). LCMS (ES⁺) 426.30 (M+H)⁺, RT 2.35 minutes.

Example 9 2-(5-{3-[2-Bromo-6-(difluoromethoxy)benzyl]-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl}pyrimidin-2-yl)propan-2-ol

Pt/C 5% type 5R163 (2 mg, 2 wt %) was added to a solution ofIntermediate 27 (100 mg, 0.181 mmol) in 1,4-dioxane (0.4 mL, 5 mmol) andthe mixture was stirred at room temperature for 18 h. The solution wasfiltered through celite, washed with 1,4-dioxane and concentrated invacuo. The residue was taken up in acetic acid (2 mL) and stirred at 50°C. for 3 h. Acetic anhydride (0.02 mL, 0.18 mmol) was added and thereaction mixture was heated at 50° C. for 72 h. The precipitate wasfiltered off and dried in vacuo. The solid was suspended in acetic acid(1 mL) and stirred at 100° C. for 2 days, then heated under microwaveirradiation for 30 minutes at 150° C. The solution was azeotroped withtoluene (2×10 mL) and taken up in DCM (10 mL). The organic solution waswashed with saturated aqueous NaHCO₃ solution (10 mL), dried with MgSO₄,filtered and concentrated in vacuo. The residue was dissolved in MeOH(0.3 mL) and cooled in an ice bath before adding NaOH (6.0 mg, 0.15mmol) in water (0.15 mL). The mixture was allowed to warm to roomtemperature and stirred for 5 h. The resulting white precipitate wasfiltered off and washed with diisopropyl ether, yielding the titlecompound (3.5 mg, 4.0%). δ_(H) (400 MHz, CDCl₃) 9.24 (s, 2H), 8.01 (d, J7.0 Hz, 1H), 7.63 (d, J 8.0 Hz, 1H), 7.56 (d, J 7.0 Hz, 1H), 7.13 (d, J8.0 Hz, 1H), 6.31 (t, J 73.3 Hz, 1H), 5.71 (s, 2H), 4.77 (s, 1H), 2.62(s, 3H), 1.65 (s, 6H). LCMS (ES+) 504.0/506.0 (M+H)⁺, RT 2.39 minutes.

Example 102-(5-{3-[2-(Difluoromethoxy)-6-fluorobenzyl]-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl}pyrimidin-2-yl)propan-2-ol

Prepared from Intermediate 30 (1.50 g, 4.39 mmol),2-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl]propan-2-ol(1.39 g, 5.26 mmol), Cs₂CO₃ (2.14 g, 6.58 mmol), 1,4-dioxane/water (9:1,25 mL) and[1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II)-dichloromethanecomplex (160.6 mg, 0.22 mmol, 5 mol %) in accordance with Method A togive the title compound (1.18 g, 60%). δ_(H) (400 MHz, CDCl₃) 9.31 (s,2H), 8.01 (d, J 8.2 Hz, 1H), 7.64 (d, J 8.2 Hz, 1H), 7.35 (dt, J 8.3,8.3 Hz, 1H), 7.04 (t, J 8.3 Hz, 1H), 6.95 (d, J 8.3 Hz, 1H), 6.44 (t, J72.8 Hz, 1H), 5.57 (s, 2H), 4.77 (s, 1H), 2.67 (s, 3H), 1.66 (s, 6H).LCMS (ES⁺) 444.0 (M+H)⁺, RT 2.26 minutes.

Example 11cis-1-(5-{3-[2-(Difluoromethoxy)-6-fluorobenzyl]-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl}pyrimidin-2-yl)-3-methylcyclobutane-1,3-diol

Intermediate 31 (215 mg, 0.36 mmol) was dissolved in dry THF (2 mL) andTBAF (1M in THF; 1.07 mL, 1.08 mmol) was added. The mixture was stirredat room temperature for 3 h. Water was added and the mixture wasextracted with EtOAc (3×10 mL). The combined organic layers were washedwith brine, dried over Na₂SO₄, filtered and concentrated in vacuo. Thecrude yellow oil was purified by column chromatography (SiO₂, gradient0-10% MeOH in EtOAc), yielding the title compound (71 mg, 40.8%). LCMS(ES⁺) 486.0 (M+H)⁺, RT 2.01 minutes.

Example 122-(5-{3-[3-Bromo-6-(difluoromethoxy)-2-fluorobenzyl]-2-methyl-3H-imidazo[4,5-b]-pyridin-5-yl}pyrimidin-2-yl)propan-2-ol

Intermediate 38 (250 mg, 0.50 mmol) was dissolved in 1,4-dioxane (2.0mL) and acetic anhydride (0.05 mL) was added. The reaction mixture wasstirred at 80° C. for 1 h, then concentrated in vacuo. The residue wastaken up in acetic acid (2 mL) and the reaction mixture was heated at150° C. for 18 h, then concentrated in vacuo. The residue was taken upin EtOAc and washed with saturated aqueous NaHCO₃ solution. The organiclayer was dried over MgSO₄, filtered and concentrated in vacuo. Thecrude residue was purified on column chromatography (SiO₂, gradient0-100% EtOAc in heptane), yielding the title compound (175 mg, 60%) as awhite solid. LCMS (ES⁺) 540.0/542.0 (M+H)⁺, RT 1.43 minutes.

Example 133-[2-(Difluoromethoxy)-6-fluorobenzyl]-2-methyl-5-{6-[S-(methyl)sulfonimidoyl]-pyridin-3-yl}-3H-imidazo[4,5-b]pyridine

Intermediate 39 (150 mg, 0.45 mmol) was dissolved in 1,4-dioxane (5 mL)and bis(pinacolato)diboron (140 mg, 0.54 mmol), potassium acetate (134mg, 1.35 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (23 mg, 0.03mmol) were added. The reaction mixture was heated at 80° C. for 2 h.Intermediate 30 (124 mg, 0.36 mmol) was added to the reaction mixture,with tri(tert-butyl)(hydrido)phosphate(1-) (13.1 mg, 0.045 mmol), water(0.22 mL), tris(dibenzylideneacetone)dipalladium(0) (3.8 mg, 0.011 mmol)and potassium carbonate (75.89 mg, 0.54 mmol). The reaction mixture washeated at 80° C. for 18 h. The mixture was cooled to room temperature,then partitioned between EtOAc (15 mL) and water (15 mL) and extractedwith EtOAc (3×10 mL). The combined organic layers were successivelywashed with saturated aqueous NH₄Cl solution and saturated aqueousNaHCO₃ solution, then dried over MgSO₄, filtered and concentrated invacuo. The crude residue was purified by preparative HPLC, yielding thetitle compound (5 mg, 2%) as a yellow solid. LCMS (ES⁺) 462.0 (M+H)⁺, RT1.21 minutes.

The invention claimed is:
 1. A compound represented by formula (IIB) oran N-oxide thereof, or a pharmaceutically acceptable salt thereof:

wherein V represents C—R²² or N; R¹² represents hydrogen, fluoro,chloro, trifluoro-methyl, methyl or ethoxycarbonylethyl; R¹⁵ representshydrogen, halogen, C₁₋₆ alkyl or difluoromethoxy; R¹⁶ representshydrogen, halogen or C₁₋₆ alkyl; R²¹ represents hydroxy(C₁₋₆)alkyl or(C₁₋₆)alkyl-sulphoximinyl; or R²¹ represents (C₃₋₇)cycloalkyl, whichgroup may be optionally substituted by one, two or three substituentsindependently selected from C₁₋₆ alkyl and hydroxy; R²² representshydrogen, halogen or C₁₋₆ alkyl; R²³ represents hydrogen, C₁₋₆ alkyl,trifluoromethyl or C₁₋₆ alkoxy; E represents —CH₂—or —CH(CH₃)—; Qrepresents —CH₂—, —CH(OH)— or —CH₂O—; Z represents hydrogen, methyl,phenyl, amino-carbonylphenyl or aminocarbonylpyridinyl.
 2. The compoundas claimed in claim 1 wherein R²¹ represents hydroxy(C₁₋₆)alkyl.
 3. Thecompound as claimed in claim 1 represented by formula (IIF), (IIG),(IIH), or (IIJ), or an N-oxide thereof, or a pharmaceutically acceptablesalt thereof:

wherein W represents C(R³²)(R³³); R³² represents hydroxy; R³³ representshydrogen or C₁₋₆ alkyl; R³⁴ represents hydrogen or hydroxy.
 4. Acompound as claimed in claim 1 wherein R¹⁵ represents difluoromethoxy.5. A compound that is2-(5-{3-[2-(Difluoromethoxy)benzyl]-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl}-pyrimidin-2-yl)propan-2-ol,2-(5-{3-[2-Bromo-6-(difluoromethoxy)benzyl]-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl}pyrimidin-2-yl)propan-2-ol,2-(5-{3-[2-(Difluoromethoxy)-6-fluorobenzyl]-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl}pyrimidin-2-yl)propan-2-ol,cis-1-(5-{3-[2-(Difluoromethoxy)-6-fluorobenzyl]-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl}pyrimidin-2-yl)-3-methylcyclobutane-1,3-diol,or3-[2-(Difluoromethoxy)-6-fluorobenzyl]-2-methyl-5-{6-[S-(methyl)sulfonimidoyl]-pyridin-3-yl}-3H-imidazo[4, 5-b]pyridine.
 6. A pharmaceutical compositioncomprising a compound of formula(IIB) as defined in claim 1 or anN-oxide thereof, or a pharmaceutically acceptable salt thereof, inassociation with a pharmaceutically acceptable carrier.
 7. Thepharmaceutical composition as claimed in claim 6 further comprising anadditional pharmaceutically active ingredient.
 8. A method of inhibitingTNFα in a subject comprising administering to said subject an effectiveamount of compound of formula (IIB) as defined in claim 1 or N-oxidethereof, or a pharmaceutically acceptable salt thereof.